Sphingolipids and Lymphomas: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Rosa López-Sánchez
,
Alfredo Pherez-Farah
,
,
Luis Villela
,
Rocio Ortiz-Lopez
,
José Ascención Hernández-Hernández

Lymphomas are a highly heterogeneous group of hematological neoplasms. Given their ethiopathogenic complexity, their classification and management can become difficult tasks; therefore, new approaches are continuously being sought. Metabolic reprogramming at the lipid level is a hot topic in cancer research, and sphingolipidomics has gained particular focus in this area due to the bioactive nature of molecules such as sphingoid bases, sphingosine-1-phosphate, ceramides, sphingomyelin, cerebrosides, globosides, and gangliosides. Sphingolipid metabolism has become especially exciting because they are involved in virtually every cellular process through an extremely intricate metabolic web; in fact, no two sphingolipids share the same fate. Unsurprisingly, a disruption at this level is a recurrent mechanism in lymphomagenesis, dissemination, and chemoresistance, which means potential biomarkers and therapeutical targets might be hiding within these pathways. 

  • lymphoma
  • cancer
  • lipid metabolism
  • lipidomics

1. Sphingoid Bases

Sphingoid bases are the simplest sphingolipids. They include sphinganine (dihydrosphingosine), which is formed from the condensation of palmitoyl-CoA and serine, and sphingosine, which results from ceramide cleavage through a ceramidase [1]. Being the backbone of larger sphingolipids, their role in cancer has not received much attention; however, they are known to have antiproliferative properties by themselves, and can enhance chemosensitivity by inducing oxidative stress and upregulating p38 and JNK in TP53 positive lymphoma cells [2][3][4][5]. In DLBCL specifically, both sphingosine and sphinganine analogues induce cell death by promoting PARP cleavage, autophagy, and PKC inhibition [6][7].

2. Sphingosine-1-Phosphate

S1P is a metabolically active form of sphingosine which results from the action of a sphingosine kinase (SPHK) [8]. When it comes to cancer, it is probably the most widely recognized sphingolipid, and it is involved in the pathogenesis of multiple neoplasms, such as head and neck, breast, ovarian, colon, pancreatic, prostate, liver, and bile duct, among many others [9][10][11][12][13][14]. It is vigorously produced by both cancer cells and cells of the tumor microenvironment, such as tumor associated macrophages (TAMs), endothelium, and fibroblasts, creating a complex “inside-out” signaling hub which promotes invasion and metastasis due to its ability to induce cell proliferation and migration, angiogenesis, and tissue remodeling [15][16][17][18][19][20]. This is achieved through the upregulation of several proto-oncogenes, such as MYC, FOS, and ABL1 [21][22][23][24]; extracellular matrix regulators, such as urokinase, Matrix Metalloprotease 2 (MMP-2), MMP-7, and syndecan-1 [25][26][27][28]; inflammatory mediators, such as IL-22 [29]; and transcription factors/transcriptional regulators, such as STAT3, MRTF-A, YAP, and SNAI2 [14][30][31]. Additionally, it favors CTFG and EGFR activation, which promote cancer cell motility through ezrin-radixin-moesin phosphorylation [32][33][34]. Moreover, it is known that autotaxin, which is upregulated in many cancers, generates many bioactive lipids, including lysophosphatidic acid (LPA) and S1P, which subsequently stimulate COX2 and therefore eicosanoid synthesis, yielding inflammatory conditions ideal for a tumorigenic microenvironment [35][36][37][38][39]. Furthermore, S1P pathways are related to chemotherapy resistance by upregulating the Multidrug Resistance gene (MDR1) [40]. This observation is consistent with the fact that SPHK1 activity and Sphingosine-1-Phosphate Receptor (S1PR) signaling appear to confer resistance to chemotherapy-induced apoptosis in many cancer models, whereas S1P-lyase, which mediates S1P degradation, has the opposite effect [41][42][43].
As for lymphomas, SPHK overexpression has consistently been associated with a more aggressive disease [44][45][46]. In vitro evidence suggests that MCL cells can evade CD1d-mediated NKT cytotoxicity by upregulating SPHK1 [47][48]. Additionally, a recent report found that SPHK1 and S1P itself mediate a VEGF-independent mechanism of angiogenesis in DLBCL, which might explain why, although some preliminary data have suggested otherwise, classical anti-angiogenic drugs such as bevacizumab are mostly ineffective for NHL [49][50][51]. These data make SPHK an attractive therapeutical target. On the other hand, it has been shown that S1PR1 signaling promotes survival, proliferation, and migration of MCL and HL cells through a PI3K-dependent pathway, and might be useful as both a pharmacological target and an marker for aggressiveness [52][53][54]. In fact, tissular expression of S1PR1 has been associated with a worse prognosis in certain NHL, particularly primary testicular DLBCL [55][56]. Interestingly, immunohistochemical detection of different S1PR isotypes, migration integrins, chemokines, and homing receptors correlates with specific anatomical and tissular locations of B-cell lymphomas [57][58][59]. For instance, in MCL, S1PR1 mutations are present in up to 8.6% of cases, and mediate tumoral cell retention in the mantle zone [60][61][62]. S1PR1 staining might be, in fact, a useful immunohistochemical marker for MCL, especially if cyclin D1 staining, the current standard, is inconclusive [63]. Additionally, it has been shown that mutations at this level (S1PR1) are partly responsible for the transformation of follicular lymphoma (FL) into its most aggressive form [64]. Contrastingly, S1PR2 activation shows completely opposite effects. Research suggests that it regulates cell survival and migration mainly through Akt and CXCL12 attenuation. In fact, the TGF-β/SMAD1/S1PR2 pathway is recurrently inactivated in DLBCL due to either disabling mutations in its axis or FOXP1-mediated downregulation [65][66][67]. Moreover, it has been recently reported that some EBV-related lymphomas downregulate S1PR2, allowing the PI3-K/Akt/mTOR pathway to be constitutively activated [68]. Naturally, while S1PR1 blockade is potentially antilymphomagenic, S1PR2 deficient mice are prone to developing DLBCL [69][70][71]. These reports highlight the complex nature of sphingolipid-related molecular pathways, and stress the need to understand them.

3. Ceramide

Ceramide is the central molecule of sphingolipid metabolism. It can be obtained by the hydrolysis of more complex sphingolipids, mainly SM via sphingomyelinase, or de novo through sphinganine fatty acylation and subsequent desaturation [1]. The length of the fatty acid chain has a relevant functional impact, being that C16, C18, and C24 are the most cytotoxic endogenously produced species. These sphingolipids are able to induce cell death through multiple pathways, including necroptosis, autophagy, mitophagy, necrosis, and especially apoptosis [72][73][74]. Caspase-dependent cell death mechanisms are achieved through Fas–FasL interaction, mitochondrial pore induction, TXNIP and BCLX upregulation, Rb overexpression, and telomere shortening via glyceraldehyde-3-phosphate dehydrogenase inhibition [75][76][77][78][79][80][81]. Furthermore, they also exhibit anti-proliferative effects through the activation of ceramide-activated protein phosphatases (CAPPs), which downregulate several CDKs; and PKC-ζ, which further leads to Akt attenuation [41][82]. This last observation is in line with the fact that ceramide and diacylglycerol (DAG), a potent PKC activator and thus pro-tumoral molecule, are simultaneously, but inversely, regulated during the SM cycle[83]. Considering all of these potentially cytotoxic mechanisms, it is not surprising that many chemotherapeutic agents exert their effects partly through intracellular ceramide accumulation in the microenvironment, and within the tumor itself [84]. Unfortunately, cancer cells can develop resistance mechanisms against this pathway. Of note, it is known that acid ceramidase, which transforms ceramides back into sphingosine, is overexpressed in multiple cancers, such as head and neck, breast, prostate, melanoma, colon, glioblastoma, leukemia, and lung, where it promotes neosis, and mediates both chemoresistance and radioresistance [41][85][86][87][88][89][90][91][92][93]. Additionally, research suggests that the Ceramide Transfer Protein (CERT), which transports ceramide from the endoplasmic reticulum to the Golgi apparatus prior to its conversion to SM, might play a key role in antineoplastic resistance, as its downregulation has been shown to enhance chemosensitivity [94].
In the particular case of lymphomas, ceramides have been shown to contribute to IL-2 deprivation related cytotoxicity by degrading the apoptotic inhibitor IAP3 through cathepsin B in T-cell and NK lymphomas [95]. Additionally, it is known that some B-cell lymphomas can have mutations in FVT1 (KDSR), a gene that codes for 3-ketodihydrosphingosine reductase, which synthesizes dehydrosphinganine, a precursor of ceramide. The fact that this locus is in close proximity to the much more recognized BCL-2 suggests a synergic role in lymphomagenesis [96]. Nonetheless, it is worth mentioning that different lymphomas have different patterns of FVT1 alterations, therefore its metabolic implications are not the same. For instance, while some FL are known to overexpress FVT1, some DLBCL downregulate it. As a matter of fact, FVT1 expression might be useful to discriminate between germinal center (GC) DLBCL from non-GC DLBCL [97]. On a different note, blocking SPHK pathways, particularly via SPHK2, is cytotoxic to murine models of primary effusion lymphoma (PEL), a human herpesvirus 8-related neoplasm, due to the upregulation of ceramide synthase and subsequent accumulation of cytotoxic ceramide species that lead to apoptosis by viral lytic gene expression [98][99]. Additionally, ceramides have also been shown to induce cell death through caspase-independent mechanisms in MCL cells, possibly due to ROS associated necrosis and ATP depletion [100][101][102]. Similar effects have been observed after treatment with ceramide analogues and exogenous ceramide administration, which induce several tumor suppressor genes such as CCL3, RHOB, KLF6, and THBS1 [103][104][105][106][107]. Finally, it is worth mentioning that rituximab, the cornerstone of B-cell NHL treatment, activates sphingomyelinase upon its binding to CD20, leading to an increased production of ceramide, and therefore selectively inducing cytotoxic pathways in CD20+ cells [108][109][110]. Similarly, it has been observed that newer anti-CD20 antibodies, such as tositumomab, are more effective in inducing programed cell death in NHL by inducing homotypic adhesion and lysosomal leakage, both of which are mediated by ceramide [95][111].

4. Ceramide-1-Phosphate

Similar to sphingosine, ceramide can also undergo phosphorylation by a ceramide kinase (CK) to produce ceramide-1-phosphate (C1P), whose functions are analogue to those of S1P and opposite to ceramide, meaning it is mainly involved in cell growth, migration, proliferation, and survival, all of which translate into cancer invasion and metastasis [1]. C1P is probably the least researched sphingolipid in the cancer context, with only a few studies linking it to neuroblastoma, and pancreatic and breast carcinomas [112]. Oncogenic and dissemination mechanisms include the PI3K/Akt/mTOR, MEK/ERK, and Rho/ROCK signaling pathways [113][114][115]. Although some of the initial studies describing the ceramide-C1P pathway were performed in leukemia cells, there is currently no published research linking C1P to lymphomas or any other hematological malignancy whatsoever [116].

5. Sphingomyelin

SM is a membrane sphingolipid that is abundantly found in membrane rafts, and thus is essential for signal transduction. In fact, K-Ras localization, and therefore MAPK/RAS signaling, is regulated by plasma membrane SM concentration [117][118]. SM results from ceramide condensation with phosphocholine via sphingomyelin synthase (SMS) [119]. As its biosynthesis requires ceramide metabolism, one might assume that these sphingolipids should have opposite effects. However, its actual role in cancer is controversial, as it is involved in both pro-tumoral and antineoplastic settings [120][121][122]. This duality might be partially explained by its central role in DAG/ceramide balance [123]. For instance, SMS2 has been shown to promote breast cancer metastasis by enhancing epithelial-to-mesenchymal transition (EMT) via TGF-β/Smad signaling [124]. On the other hand, SM levels seem to be inversely correlated with many cancer types, such as lung and esophageal [112][123]. Furthermore, exogenous SM administration promotes PPAR-γ mediated Th2 and anti-inflammatory responses, which are protective against cancer, and enhances chemotherapy-induced cytotoxicity by promoting drug influx and bioavailability [85][125][126][127].
In lymphomas most research points towards a primarily pro-tumorigenic effect. In vitro models have shown that SMS overexpression induces apoptosis resistance through PI3K-Akt upregulation, and stimulates malignant proliferation by promoting transferrin endocytosis in a SM-dependent manner [128]. These findings are in line with the fact that SMS inhibition or blockade enhances cell death due to ceramide accumulation, and inhibits infiltration by hindering the NF-κB pathway, subsequently downregulating adhesion molecules such as ICAM-1 [121][129]. On a different note, a recent clinical study found that even though total serum SM was similar between healthy controls and patients with hematologic malignancies, there were significantly lower levels of odd chain saturated fatty acids (OCFA) in the latter, which is interesting, since OCFA have recently been reported to be protective against several neoplasms, probably due to their histone deacetylase 6 inhibitor activity [130][131][132][133][134]. Finally, it has been observed that some lipid fragments of SM, together with specific phospholipid patterns, such as increased phosphatidylinositol and phosphatidylcholine, are markers of R-CHOP resistant or relapsed cases and of hypoxic and/or necrotic regions within the tumor [135]. These findings align with the previous observation that some endogenously produced phosphatidyl-myoinositols serve as physiologic inhibitors of sphingomyelinase [136].

6. Glycosphingolipids

GSLs are highly specialized, saccharide-containing sphingolipids that result from sequential glycosylation reactions from ceramide. This group includes cerebrosides, globosides, and gangliosides. GSLs are the core structures of glycosphingolipid enriched microdomains (GEMs) and glycosynapses, meaning they have a central role in signal recognition and transduction, and mediate complex cellular interactions [137]. Being such a large sphingolipid subfamily, GSLs’ effects on cancer can be strikingly diverse, and have been extensively researched in this area [138][139]. It is known that many GSLs are differentially found in several solid malignancies, such as cholangiocarcinoma and ovarian cancer, and some of them have even been proposed as potential biomarkers for these tumors [140][141][142][143][144]. This differential expression, along with the fact that during malignant transformation they undergo cancer-specific modifications such as fucosylation, has allowed for the development of promising targeted immunotherapies, including monoclonal antibodies, vaccines, and CAR-T cells against aggressive malignancies such as neuroblastoma, retinoblastoma, and Ewing’s sarcoma [145][146][147][148][149][150].

This entry is adapted from the peer-reviewed paper 10.3390/cancers14092051

References

  1. Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat. Cancer 2017, 18, 33–50.
  2. Farhat, M.; Poissonnier, A.; Hamze, A.; Ouk-Martin, C.; Brion, J.-D.; Alami, M.; Feuillard, J.; Jayatvignoles, C. Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases. Cell Death Dis. 2014, 5, e1201.
  3. Song, M.M.; Makena, M.R.; Hindle, A.; Koneru, B.; Nguyen, T.H.; Verlekar, D.U.; Cho, H.; Maurer, B.J.; Kang, M.H.; Reynolds, C.P. Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. Anti-Cancer Drugs 2019, 30, 117–127.
  4. Ahn, E.H.; Chang, C.-C.; Schroeder, J.J. Evaluation of Sphinganine and Sphingosine as Human Breast Cancer Chemotherapeutic and Chemopreventive Agents. Exp. Biol. Med. 2006, 231, 1664–1672.
  5. Ahn, E.H.; Yang, H.; Hsieh, C.-Y.; Sun, W.; Chang, C.-C.; Schroeder, J.J. Evaluation of chemotherapeutic and cancer-protective properties of sphingosine and C2-ceramide in a human breast stem cell derived carcinogenesis model. Int. J. Oncol. 2019, 54, 655–664.
  6. Bode, C.; Berlin, M.; Röstel, F.; Teichmann, B.; Gräler, M.H. Evaluating Sphingosine and its Analogues as Potential Alternatives for Aggressive Lymphoma Treatment. Cell. Physiol. Biochem. 2014, 34, 1686–1700.
  7. Park, M.-T.; Kang, J.A.; Choi, J.-A.; Kang, C.-M.; Kim, T.-H.; Bae, S.; Kang, S.; Kim, S.; Choi, W.-I.; Cho, C.-K.; et al. Phytosphingosine induces apoptotic cell death via caspase 8 activation and Bax translocation in human cancer cells. Clin. Cancer Res. 2003, 9, 878–885.
  8. Hannun, Y.A.; Obeid, L.M. Sphingolipids and their metabolism in physiology and disease. Nat. Rev. Mol. Cell Biol. 2018, 19, 175–191.
  9. Yuza, K.; Nakajima, M.; Nagahashi, M.; Tsuchida, J.; Hirose, Y.; Miura, K.; Tajima, Y.; Abe, M.; Sakimura, K.; Takabe, K.; et al. Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression. J. Surg. Res. 2018, 232, 186–194.
  10. Tsuchida, J.; Nagahashi, M.; Nakajima, M.; Moro, K.; Tatsuda, K.; Ramanathan, R.; Takabe, K.; Wakai, T. Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis. J. Surg. Res. 2016, 205, 85–94.
  11. Hirose, Y.; Nagahashi, M.; Katsuta, E.; Yuza, K.; Miura, K.; Sakata, J.; Kobayashi, T.; Ichikawa, H.; Shimada, Y.; Kameyama, H.; et al. Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis. Sci. Rep. 2018, 8, 10814.
  12. Nunes, J.; Naymark, M.; Sauer, L.; Muhammad, A.; Keun, H.; Sturge, J.; Stebbing, J.; Waxman, J.; Pchejetski, D. Circulating sphingosine-1-phosphate and erythrocyte sphingosine kinase-1 activity as novel biomarkers for early prostate cancer detection. Br. J. Cancer 2012, 106, 909–915.
  13. Yokota, T.; Nojima, H.; Kuboki, S.; Yoshitomi, H.; Furukawa, K.; Takayashiki, T.; Takano, S.; Ohtsuka, M. Sphingosine-1-phosphate Receptor-1 Promotes Vascular Invasion and EMT in Hepatocellular Carcinoma. J. Surg. Res. 2021, 259, 200–210.
  14. Fan, Q.; Cheng, Y.; Chang, H.-M.; Deguchi, M.; Hsueh, A.J.; Leung, P.C.K. Sphingosine-1-phosphate promotes ovarian cancer cell proliferation by disrupting Hippo signaling. Oncotarget 2017, 8, 27166–27176.
  15. Nakajima, M.; Nagahashi, M.; Rashid, O.; Takabe, K.; Wakai, T. The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications. Tumor Biol. 2017, 39, 1010428317699133.
  16. Riboni, L.; Hadi, L.A.; Navone, S.E.; Guarnaccia, L.; Campanella, R.; Marfia, G. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks. Cells 2020, 9, 337.
  17. Rodriguez, Y.I.; Campos, L.E.; Castro, M.G.; Aladhami, A.; Oskeritzian, C.A.; Alvarez, S.E. Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment. Front. Oncol. 2016, 6, 218.
  18. Weichand, B.; Popp, R.; Dziumbla, S.; Mora, J.; Strack, E.; Elwakeel, E.; Frank, A.-C.; Scholich, K.; Pierre, S.; Syed, S.N.; et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J. Exp. Med. 2017, 214, 2695–2713.
  19. El Buri, A.; Adams, D.R.; Smith, D.; Tate, R.; Mullin, M.; Pyne, S.; Pyne, N.J. The sphingosine 1-phosphate receptor 2 is shed in exosomes from breast cancer cells and is N-terminally processed to a short constitutively active form that promotes extracellular signal regulated kinase activation and DNA synthesis in fibroblasts. Oncotarget 2018, 9, 29453–29467.
  20. Albinet, V.; Bats, M.-L.; Huwiler, A.; Rochaix, P.; Chevreau, C.; Ségui, B.; Levade, T.; Andrieu-Abadie, N. Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells. Oncogene 2014, 33, 3364–3373.
  21. Yester, J.W.; Bryan, L.; Waters, M.R.; Mierzenski, B.; Biswas, D.D.; Gupta, A.S.; Bhardwaj, R.; Surace, M.J.; Eltit, J.M.; Milstien, S.; et al. Sphingosine-1-phosphate inhibits IL-1-induced expression of C-C motif ligand 5 via c-Fos-dependent suppression of IFN-β amplification loop. FASEB J. 2015, 29, 4853–4865.
  22. Zhang, S.; Huang, P.; Dai, H.; Li, Q.; Hu, L.; Peng, J.; Jiang, S.; Xu, Y.; Wu, Z.; Nie, H.; et al. TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer. Cell Death Dis. 2020, 11, 1–14.
  23. Bi, Y.; Li, J.; Ji, B.; Kang, N.; Yang, L.; Simonetto, D.A.; Kwon, J.H.; Kamath, M.; Cao, S.; Shah, V. Sphingosine-1-Phosphate Mediates a Reciprocal Signaling Pathway between Stellate Cells and Cancer Cells that Promotes Pancreatic Cancer Growth. Am. J. Pathol. 2014, 184, 2791–2802.
  24. Shen, Y.; Zhao, S.; Wang, S.; Pan, X.; Zhang, Y.; Xu, J.; Jiang, Y.; Li, H.; Zhang, Q.; Gao, J.; et al. S1P/S1PR3 axis promotes aerobic glycolysis by YAP/c-MYC/PGAM1 axis in osteosarcoma. EBioMedicine 2019, 40, 210–223.
  25. Ko, P.; Kim, D.; You, E.; Jung, J.; Oh, S.; Kim, J.; Lee, K.-H.; Rhee, S. Extracellular Matrix Rigidity-dependent Sphingosine-1-phosphate Secretion Regulates Metastatic Cancer Cell Invasion and Adhesion. Sci. Rep. 2016, 6, 21564.
  26. Zeng, Y.; Liu, X.; Yan, Z.; Xie, L. Sphingosine 1-phosphate regulates proliferation, cell cycle and apoptosis of hepatocellular carcinoma cells via syndecan-1. Prog. Biophys. Mol. Biol. 2019, 148, 32–38.
  27. Sassoli, C.; Pierucci, F.; Tani, A.; Frati, A.; Chellini, F.; Matteini, F.; Vestri, A.; Anderloni, G.; Nosi, D.; Zecchi-Orlandini, S.; et al. Sphingosine 1-Phosphate Receptor 1 Is Required for MMP-2 Function in Bone Marrow Mesenchymal Stromal Cells: Implications for Cytoskeleton Assembly and Proliferation. Stem Cells Int. 2018, 2018, 1–18.
  28. Young, N.; Pearl, D.K.; Van Brocklyn, J.R. Sphingosine-1-Phosphate Regulates Glioblastoma Cell Invasiveness through the Urokinase Plasminogen Activator System and CCN1/Cyr61. Mol. Cancer Res. 2009, 7, 23–32.
  29. Kim, E.-Y.; Choi, B.; Kim, J.-E.; Park, S.-O.; Kim, S.-M.; Chang, E.-J. Interleukin-22 Mediates the Chemotactic Migration of Breast Cancer Cells and Macrophage Infiltration of the Bone Microenvironment by Potentiating S1P/SIPR Signaling. Cells 2020, 9, 131.
  30. Liang, J.; Nagahashi, M.; Kim, E.Y.; Harikumar, K.B.; Yamada, A.; Huang, W.-C.; Hait, N.C.; Allegood, J.C.; Price, M.M.; Avni, D.; et al. Sphingosine-1-Phosphate Links Persistent STAT3 Activation, Chronic Intestinal Inflammation, and Development of Colitis-Associated Cancer. Cancer Cell 2013, 23, 107–120.
  31. Wang, W.; Hind, T.; Lam, B.W.S.; Herr, D.R. Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells. FASEB J. 2019, 33, 7180–7191.
  32. Cattaneo, M.G.; Vanetti, C.; Samarani, M.; Aureli, M.; Bassi, R.; Sonnino, S.; Giussani, P. Cross-talk between sphingosine-1-phosphate and EGFR signaling pathways enhances human glioblastoma cell invasiveness. FEBS Lett. 2018, 592, 949–961.
  33. Adada, M.M.; Canals, D.; Jeong, N.; Kelkar, A.D.; Hernandez-Corbacho, M.; Pulkoski-Gross, M.J.; Donaldson, J.C.; Hannun, Y.A.; Obeid, L.M. Intracellular sphingosine kinase 2-derived sphingosine-1-phosphate mediates epidermal growth factor-induced ezrin-radixin-moesin phosphorylation and cancer cell invasion. FASEB J. 2015, 29, 4654–4669.
  34. Muehlich, S. Induction of connective tissue growth factor (CTGF) in human endothelial cells by lysophosphatidic acid, sphingosine-1-phosphate, and platelets. Atherosclerosis 2004, 175, 261–268.
  35. Patwardhan, G.A.; Liu, Y.-Y. Sphingolipids and expression regulation of genes in cancer. Prog. Lipid Res. 2011, 50, 104–114.
  36. Snider, A.J.; Gandy, K.A.O.; Obeid, L.M. Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 2010, 92, 707–715.
  37. Ségui, B.; Andrieu-Abadie, N.; Jaffrézou, J.-P.; Benoist, H.; Levade, T. Sphingolipids as modulators of cancer cell death: Potential therapeutic targets. Biochim. et Biophys. Acta (BBA)-Biomembr. 2006, 1758, 2104–2120.
  38. Koike, S.; Keino-Masu, K.; Ohto, T.; Masu, M. The N-terminal hydrophobic sequence of autotaxin (ENPP2) functions as a signal peptide. Genes Cells 2006, 11, 133–142.
  39. Härmä, V.; Knuuttila, M.; Virtanen, J.; Mirtti, T.; Kohonen, P.; Kovanen, P.; Happonen, A.; Kaewphan, S.; Ahonen, I.; Kallioniemi, O.; et al. Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models. Oncogene 2012, 31, 2075–2089.
  40. Yamada, A.; Nagahashi, M.; Aoyagi, T.; Huang, W.-C.; Lima, S.; Hait, N.C.; Maiti, A.; Kida, K.; Terracina, K.P.; Miyazaki, H.; et al. ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer. Mol. Cancer Res. 2018, 16, 1059–1070.
  41. Saddoughi, S.A.; Song, P.; Ogretmen, B. Roles of Bioactive Sphingolipids in Cancer Biology and Therapeutics. In Lipids in Health and Disease; Springer: Dordrecht, The Netherlands, 2008; pp. 413–440.
  42. Ihlefeld, K.; Vienken, H.; Claas, R.F.; Blankenbach, K.; Rudowski, A.; ter Braak, M.; Koch, A.; Van Veldhoven, P.P.; Pfeilschifter, J.; zu Heringdorf, D.M. Upregulation of ABC transporters contributes to chemoresistance of sphingosine 1-phosphate lyase-deficient fibroblasts. J. Lipid Res. 2015, 56, 60–69.
  43. Matula, K.; Collie-Duguid, E.; Murray, G.; Parikh, K.; Grabsch, H.; Tan, P.; Lalwani, S.; Garau, R.; Ong, Y.; Bain, G.; et al. Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer. BMC Cancer 2015, 15, 1–14.
  44. Pyne, N.J.; Pyne, S. Recent advances in the role of sphingosine 1-phosphate in cancer. FEBS Lett. 2020, 594, 3583–3601.
  45. Le, Y.; Shen, X.; Kang, H.; Wang, Q.; Li, K.; Zheng, J.; Yu, Y. Accelerated, untargeted metabolomics analysis of cutaneous T-cell lymphoma reveals metabolic shifts in plasma and tumor adjacent skins of xenograft mice. Biol. Mass Spectrom. 2018, 53, 172–182.
  46. Bayerl, M.G.; Bruggeman, R.D.; Conroy, E.J.; Hengst, J.A.; King, T.S.; Jimenez, M.; Claxton, D.F.; Yun, J.K. Sphingosine kinase 1 protein and mRNA are overexpressed in non-Hodgkin lymphomas and are attractive targets for novel pharmacological interventions. Leuk. Lymphoma 2008, 49, 948–954.
  47. Lee, M.S.; Sun, W.; Webb, T.J. Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma. Cells 2020, 9, 1030.
  48. Bagchi, S.; Li, S.; Wang, C.-R. CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b+ T cell lymphoma. OncoImmunology 2016, 5, e1213932.
  49. Lupino, L.; Perry, T.; Margielewska, S.; Hollows, R.; Ibrahim, M.; Care, M.; Allegood, J.; Tooze, R.; Sabbadini, R.; Reynolds, G.; et al. Sphingosine-1-phosphate signalling drives an angiogenic transcriptional programme in diffuse large B cell lymphoma. Leukemia 2019, 33, 2884–2897.
  50. Seymour, J.F.; Pfreundschuh, M.; Trnĕný, M.; Sehn, L.H.; Catalano, J.; Csinady, E.; Moore, N.; Coiffier, B.; on behalf of the MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: Final MAIN study outcomes. Haematologica 2014, 99, 1343–1349.
  51. Solimando, A.; Annese, T.; Tamma, R.; Ingravallo, G.; Maiorano, E.; Vacca, A.; Specchia, G.; Ribatti, D. New Insights into Diffuse Large B-Cell Lymphoma Pathobiology. Cancers 2020, 12, 1869.
  52. Kluk, M.J.; Ryan, K.P.; Wang, B.; Zhang, G.; Rodig, S.J.; Sanchez, T. Sphingosine-1-phosphate receptor 1 in classical Hodgkin lymphoma: Assessment of expression and role in cell migration. Lab. Investig. 2013, 93, 462–471.
  53. Wang, Y.; Zhang, Z.; Wan, W.; Liu, Y.; Jing, H.; Dong, F. FAM19A5/S1PR1 signaling pathway regulates the viability and proliferation of mantle cell lymphoma. J. Recept. Signal Transduct. 2021, 1–5.
  54. Rao, S.; Cai, K.Q.; Stadanlick, J.E.; Greenberg-Kushnir, N.; Solanki-Patel, N.; Lee, S.-Y.; Fahl, S.; Testa, J.R.; Wiest, D.L. Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma. Cancer Res. 2016, 76, 3387–3396.
  55. Koresawa, R.; Yamazaki, K.; Oka, D.; Fujiwara, H.; Nishimura, H.; Akiyama, T.; Hamasaki, S.; Wada, H.; Sugihara, T.; Sadahira, Y. Sphingosine-1-phosphate receptor 1 as a prognostic biomarker and therapeutic target for patients with primary testicular diffuse large B-cell lymphoma. Br. J. Haematol. 2016, 174, 264–274.
  56. Paik, J.H.; Nam, S.J.; Kim, T.M.; Heo, D.S.; Kim, C.-W.; Jeon, Y.K. Overexpression of sphingosine-1-phosphate receptor 1 and phospho-signal transducer and activator of transcription 3 is associated with poor prognosis in rituximab-treated diffuse large B-cell lymphomas. BMC Cancer 2014, 14, 1–10.
  57. Middle, S.; Coupland, S.E.; Taktak, A.; Kidgell, V.; Slupsky, J.R.; Pettitt, A.R.; Till, K.J. Immunohistochemical analysis indicates that the anatomical location of B-cell non-Hodgkin’s lymphoma is determined by differentially expressed chemokine receptors, sphingosine-1-phosphate receptors and integrins. Exp. Hematol. Oncol. 2015, 4, 10.
  58. Al-Kawaaz, M.; Sanchez, T.; Kluk, M.J. Evaluation of S1PR1, pSTAT3, S1PR2, and FOXP1 expression in aggressive, mature B cell lymphomas. J. Hematop. 2019, 12, 57–65.
  59. Nedelkovska, H.; Rosenberg, A.F.; Hilchey, S.P.; Hyrien, O.; Burack, W.R.; Quataert, S.A.; Baker, C.M.; Azadniv, M.; Welle, S.L.; Ansell, S.M.; et al. Follicular Lymphoma Tregs Have a Distinct Transcription Profile Impacting Their Migration and Retention in the Malignant Lymph Node. PLoS ONE 2016, 11, e0155347.
  60. Wasik, A.M.; Wu, C.; Mansouri, L.; Rosenquist, R.; Pan-Hammarstrom, Q.; Sander, B. Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma. Blood Adv. 2018, 2, 621–625.
  61. Hill, H.A.; Qi, X.; Jain, P.; Nomie, K.; Wang, Y.; Zhou, S.; Wang, M.L. Genetic mutations and features of mantle cell lymphoma: A systematic review and meta-analysis. Blood Adv. 2020, 4, 2927–2938.
  62. Sadeghi, L.; Arvidsson, G.; Merrien, M.; Wasik, A.M.; Görgens, A.; Smith, C.E.; Sander, B.; Wright, A.P. Differential B-Cell Receptor Signaling Requirement for Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells. Cancers 2020, 12, 1143.
  63. Nishimura, H.; Akiyama, T.; Monobe, Y.; Matsubara, K.; Igarashi, Y.; Abe, M.; Sugihara, T.; Sadahira, Y. Expression of sphingosine-1-phosphate receptor 1 in mantle cell lymphoma. Mod. Pathol. 2010, 23, 439–449.
  64. Bouska, A.; Zhang, W.; Gong, Q.; Iqbal, J.; Scuto, A.; Vose, J.; Ludvigsen, M.; Fu, K.; Weisenburger, D.D.; Greiner, T.C.; et al. Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma. Leukemia 2017, 31, 83–91.
  65. Stelling, A.; Hashwah, H.; Bertram, K.; Manz, M.; Tzankov, A.; Müller, A. The tumor suppressive TGF-β/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. Blood 2018, 131, 2235–2246.
  66. Flori, M.; Schmid, C.A.; Sumrall, E.T.; Tzankov, A.; Law, C.W.; Robinson, M.; Müller, A. The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling. Blood 2016, 127, 1438–1448.
  67. Orgueira, A.M.; Ferro, R.F.; Arias, J.D.; Santos, C.A.; Rodríguez, B.A.; Pérez, L.B.; Vence, N.A.; López, B.; Blanco, A.A.; Valentín, P.M.; et al. Detection of new drivers of frequent B-cell lymphoid neoplasms using an integrated analysis of whole genomes. PLoS ONE 2021, 16, e0248886.
  68. Vockerodt, M.; Vrzalikova, K.; Ibrahim, M.; Nagy, E.; Margielewska, S.; Hollows, R.; Lupino, L.; Tooze, R.; Care, M.; Simmons, W.; et al. Regulation of S1PR2 by the EBV oncogene LMP1 in aggressive ABC-subtype diffuse large B-cell lymphoma. J. Pathol. 2019, 248, 142–154.
  69. Green, J.A.; Suzuki, K.; Cho, B.; Willison, L.D.; Palmer, D.; Allen, C.D.C.; Schmidt, T.H.; Xu, Y.; Proia, R.L.; Coughlin, S.R.; et al. The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement. Nat. Immunol. 2011, 12, 672–680.
  70. Cattoretti, G.; Mandelbaum, J.; Lee, N.; Chaves, A.H.; Mahler, A.M.; Chadburn, A.; Dalla-Favera, R.; Pasqualucci, L.; MacLennan, A.J. Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation. Cancer Res. 2009, 69, 8686–8692.
  71. Muppidi, J.; Schmitz, R.; Green, J.A.; Xiao, W.; Larsen, A.B.; Braun, S.E.; An, J.; Xu, Y.; Rosenwald, A.; Ott, G.; et al. Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma. Nature 2014, 516, 254–258.
  72. Castro, B.M.; Prieto, M.; Silva, L.C. Ceramide: A simple sphingolipid with unique biophysical properties. Prog. Lipid Res. 2014, 54, 53–67.
  73. Nganga, R.; Oleinik, N.; Ogretmen, B. Mechanisms of Ceramide-Dependent Cancer Cell Death. Adv Cancer Res. 2018, 140, 1–25.
  74. Hait, N.C.; Maiti, A. The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer. Mediat. Inflamm. 2017, 2017, 1–17.
  75. Abou-Ghali, M.; Stiban, J. Regulation of ceramide channel formation and disassembly: Insights on the initiation of apoptosis. Saudi J. Biol. Sci. 2015, 22, 760–772.
  76. Hetz, C.A.; Hunn, M.; Rojas, P.; Torres, V.; Leyton, L.; Quest, A.F.G. Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: Onset of necrosis is associated with delayed ceramide increase. J. Cell Sci. 2002, 115, 4671–4683.
  77. Govindarajah, N.; Clifford, R.; Bowden, D.; Sutton, P.; Parsons, J.; Vimalachandran, D. Sphingolipids and acid ceramidase as therapeutic targets in cancer therapy. Crit. Rev. Oncol. 2019, 138, 104–111.
  78. Cremesti, A.; Paris, F.; Grassmé, H.; Holler, N.; Tschopp, J.; Fuks, Z.; Gulbins, E.; Kolesnick, R. Ceramide Enables Fas to Cap and Kill. J. Biol. Chem. 2001, 276, 23954–23961.
  79. Chalfant, C.E.; Rathman, K.; Pinkerman, R.L.; Wood, R.E.; Obeid, L.M.; Ogretmen, B.; Hannun, Y.A. De Novo Ceramide Regulates the Alternative Splicing of Caspase 9 and Bcl-x in A549 Lung Adenocarcinoma Cells. Dependence on protein phosphatase-1. J. Biol. Chem. 2002, 277, 12587–12595.
  80. Chang, W.-T.; Wu, C.-Y.; Lin, Y.-C.; Wu, M.-T.; Su, K.-L.; Yuan, S.-S.; Wang, H.-M.D.; Fong, Y.; Lin, Y.-H.; Chiu, C.-C. C2-Ceramide-Induced Rb-Dominant Senescence-Like Phenotype Leads to Human Breast Cancer MCF-7 Escape from p53-Dependent Cell Death. Int. J. Mol. Sci. 2019, 20, 4292.
  81. Sundararaj, K.P.; Wood, R.E.; Ponnusamy, S.; Salas, A.M.; Szulc, Z.; Bielawska, A.; Obeid, L.M.; Hannun, Y.A.; Ogretmen, B. Rapid Shortening of Telomere Length in Response to Ceramide Involves the Inhibition of Telomere Binding Activity of Nuclear Glyceraldehyde-3-phosphate Dehydrogenase. J. Biol. Chem. 2004, 279, 6152–6162.
  82. Chalfant, C.E.; Kishikawa, K.; Mumby, M.C.; Kamibayashi, C.; Bielawska, A.; Hannun, Y.A. Long Chain Ceramides Activate Protein Phosphatase-1 and Protein Phosphatase-2A. J. Biol. Chem. 1999, 274, 20313–20317.
  83. Ruvolo, P. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 2001, 15, 1153–1160.
  84. Nepali, P.R.; Haimovitz-Friedman, A. Chemotherapeutic Agents-Induced Ceramide-Rich Platforms (CRPs) in Endothelial Cells and Their Modulation. In Methods in Molecular Biology; Springer: New York, NY, USA, 2020.
  85. Furuya, H.; Shimizu, Y.; Kawamori, T. Sphingolipids in cancer. Cancer Metastasis Rev. 2011, 30, 567–576.
  86. Schiffmann, S.; Sandner, J.; Birod, K.; Wobst, I.; Angioni, C.; Ruckhäberle, E.; Kaufmann, M.; Ackermann, H.; Lötsch, J.; Schmidt, H.; et al. Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis 2009, 30, 745–752.
  87. Roh, J.-L.; Park, J.Y.; Kim, E.H.; Jang, H.J. Targeting acid ceramidase sensitises head and neck cancer to cisplatin. Eur. J. Cancer 2016, 52, 163–172.
  88. White-Gilbertson, S.; Lu, P.; Norris, J.S.; Voelkel-Johnson, C. Genetic and pharmacological inhibition of acid ceramidase prevents asymmetric cell division by neosis. J. Lipid Res. 2019, 60, 1225–1235.
  89. Cheng, J.C.; Bai, A.; Beckham, T.H.; Tucker Marrison, S.; Yount, C.L.; Young, K.; Lu, P.; Bartlett, A.M.; Wu, B.X.; Keane, B.J.; et al. Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J. Clin. Investig. 2013, 123, 4344–4358.
  90. Realini, N.; Palese, F.; Pizzirani, D.; Pontis, S.; Basit, A.; Bach, A.; Ganesan, A.; Piomelli, D. Acid Ceramidase in Melanoma. J. Biol. Chem. 2016, 291, 2422–2434.
  91. Klobučar, M.; Grbčić, P.; Pavelić, S.K.; Jonjić, N.; Visentin, S.; Sedić, M. Acid ceramidase inhibition sensitizes human colon cancer cells to oxaliplatin through downregulation of transglutaminase 2 and β1 integrin/FAK−mediated signalling. Biochem. Biophys. Res. Commun. 2018, 503, 843–848.
  92. Doan, N.B.; Nguyen, H.S.; Al-Gizawiy, M.M.; Mueller, W.M.; Sabbadini, R.A.; Rand, S.D.; Connelly, J.M.; Chitambar, C.R.; Schmainda, K.; Mirza, S.P. Acid ceramidase confers radioresistance to glioblastoma cells. Oncol. Rep. 2017, 38, 1932–1940.
  93. Tan, S.-F.; Pearson, J.M.; Feith, D.J.; Loughran, T.P. The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia. Expert Opin. Ther. Targets 2017, 21, 583–590.
  94. Swanton, C.; Marani, M.; Pardo, O.; Warne, P.H.; Kelly, G.; Sahai, E.; Elustondo, F.; Chang, J.; Temple, J.; Ahmed, A.A.; et al. Regulators of Mitotic Arrest and Ceramide Metabolism Are Determinants of Sensitivity to Paclitaxel and Other Chemotherapeutic Drugs. Cancer Cell 2007, 11, 498–512.
  95. Taniguchi, M.; Ogiso, H.; Takeuchi, T.; Kitatani, K.; Umehara, H.; Okazaki, T. Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis. Cell Death Dis. 2015, 6, e1717.
  96. Rimokh, R.; Gadoux, M.; Bertheas, M.; Berger, F.; Garoscio, M.; Deleage, G.; Germain, D.; Magaud, J. FVT-1, a novel human transcription unit affected by variant translocation t(2;18)(p11;q21) of follicular lymphoma. Blood 1993, 81, 136–142.
  97. Czuchlewski, D.R.; Csernus, B.; Bubman, D.; Hyjek, E.; Martin, P.; Chadburn, A.; Knowles, D.M.; Cesarman, E. Expression of the Follicular Lymphoma Variant Translocation 1 Gene in Diffuse Large B-Cell Lymphoma Correlates With Subtype and Clinical Outcome. Am. J. Clin. Pathol. 2008, 130, 957–962.
  98. Dai, L.; Trillo-Tinoco, J.; Bai, A.; Chen, Y.; Bielawski, J.; Del Valle, L.; Smith, C.D.; Ochoa, A.C.; Qin, Z.; Parsons, C. Ceramides promote apoptosis for virus-infected lymphoma cells through induction of ceramide synthases and viral lytic gene expression. Oncotarget 2015, 6, 24246–24260.
  99. Qin, Z.; Dai, L.; Trillo-Tinoco, J.; Senkal, C.; Wang, W.; Reske, T.; Bonstaff, K.; Del Valle, L.; Rodriguez, P.; Flemington, E.; et al. Targeting Sphingosine Kinase Induces Apoptosis and Tumor Regression for KSHV-Associated Primary Effusion Lymphoma. Mol. Cancer Ther. 2013, 13, 154–164.
  100. Huang, Y.; Wu, S.; Zhang, Y.; Zi, Y.; Yang, M.; Guo, Y.; Zhang, L.; Wang, L. Ceramide participates in cell programmed death induced by Type II anti-CD20 mAb. J. Cent. South Univ. Med. Sci. 2015, 40, 1292–1297.
  101. Gustafsson, K.; Sander, B.; Bielawski, J.; Hannun, Y.A.; Flygare, J. Potentiation of Cannabinoid-Induced Cytotoxicity in Mantle Cell Lymphoma through Modulation of Ceramide Metabolism. Mol. Cancer Res. 2009, 7, 1086–1098.
  102. Villena, J.; Henriquez, M.; Torres, V.; Moraga, F.; Díaz-Elizondo, J.; Arredondo, C.; Chiong, M.; Olea-Azar, C.; Stutzin, A.; Lavandero, S.; et al. Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells. Free Radic. Biol. Med. 2008, 44, 1146–1160.
  103. Chen, J.; Goyal, N.; Dai, L.; Lin, Z.; Del Valle, L.; Zabaleta, J.; Liu, J.; Post, S.R.; Foroozesh, M.; Qin, Z. Developing new ceramide analogs and identifying novel sphingolipid-controlled genes against a virus-associated lymphoma. Blood 2020, 136, 2175–2187.
  104. Cao, Y.; Qiao, J.; Lin, Z.; Zabaleta, J.; Dai, L.; Qin, Z. Up-regulation of tumor suppressor genes by exogenous dhC16-Cer contributes to its anti-cancer activity in primary effusion lymphoma. Oncotarget 2017, 8, 15220–15229.
  105. Wilhelm, R.; Eckes, T.; Imre, G.; Kippenberger, S.; Meissner, M.; Thomas, D.; Trautmann, S.; Merlio, J.-P.; Chevret, E.; Kaufmann, R.; et al. C6 Ceramide (d18:1/6:0) as a Novel Treatment of Cutaneous T Cell Lymphoma. Cancers 2021, 13, 270.
  106. Voorzanger-Rousselot, N.; Alberti, L.; Blay, J.-Y. CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer 2006, 6, 75.
  107. Dai, L.; Bai, A.; Smith, C.D.; Rodriguez, P.C.; Yu, F.; Qin, Z. ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus–Infected Cell Autophagic Death and Represses Tumor Growth. Mol. Cancer Ther. 2017, 16, 2724–2734.
  108. Bezombes, C.; Grazide, S.; Garret, C.; Fabre, C.; Quillet-Mary, A.; Müller, S.; Jaffrézou, J.-P.; Laurent, G. Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains. Blood 2004, 104, 1166–1173.
  109. Ren, H.; Zhang, C.; Su, L.; Bi, X.; Wang, C.; Wang, L.; Wu, B. Type II anti-CD20 mAb-induced lysosome mediated cell death is mediated through a ceramide-dependent pathway. Biochem. Biophys. Res. Commun. 2015, 457, 572–577.
  110. Liu, Y.; Shu, L.; Wu, J. Ceramide participates in lysosome-mediated cell death induced by type II anti-CD20 monoclonal antibodies. Leuk. Lymphoma 2015, 56, 1–6.
  111. Alduaij, W.; Ivanov, A.; Honeychurch, J.; Cheadle, E.J.; Potluri, S.; Lim, S.H.; Shimada, K.; Chan, C.H.T.; Tutt, A.; Beers, S.A.; et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 2011, 117, 4519–4529.
  112. Codini, M.; Garcia-Gil, M.; Albi, E. Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer. Int. J. Mol. Sci. 2021, 22, 726.
  113. Gomez-Larrauri, A.; Ouro, A.; Trueba, M.; Gomez-Muñoz, A. Regulation of cell growth, survival and migration by ceramide 1-phosphate-implications in lung cancer progression and inflammation. Cell. Signal. 2021, 83, 109980.
  114. Rivera, I.; Ordoñez, M.; Presa, N.; Gangoiti, P.; Gomez-Larrauri, A.; Trueba, M.; Fox, T.; Kester, M.; Muñoz, A.G. Ceramide 1-phosphate regulates cell migration and invasion of human pancreatic cancer cells. Biochem. Pharmacol. 2015, 102, 107–119.
  115. Schwalm, S.; Erhardt, M.; Römer, I.; Pfeilschifter, J.; Zangemeister-Wittke, U.; Huwiler, A. Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt. Int. J. Mol. Sci. 2020, 21, 1396.
  116. Dressler, K.; Kolesnick, R. Ceramide 1-phosphate, a novel phospholipid in human leukemia (HL-60) cells. Synthesis via ceramide from sphingomyelin. J. Biol. Chem. 1990, 265, 14917–14921.
  117. van der Hoeven, D.; Cho, K.-J.; Zhou, Y.; Ma, X.; Chen, W.; Naji, A.; Montufar-Solis, D.; Zuo, Y.; Kovar, S.E.; Levental, K.R.; et al. Sphingomyelin Metabolism Is a Regulator of K-Ras Function. Mol. Cell. Biol. 2017, 38, e00373-17.
  118. Yerly, S.; Ding, H.; Tauzin, S.; Van Echten-Deckert, G.; Borisch, B.; Hoessli, D.C. The sphingolipid-rich rafts of ALK+ lymphomas downregulate the Lyn-Cbp/PAG signalosome. Eur. J. Haematol. 2010, 85, 93–98.
  119. Olson, D.; Fröhlich, F.; Farese, R.; Walther, T. Taming the sphinx: Mechanisms of cellular sphingolipid homeostasis. Biochim. et Biophys. Acta (BBA)-Mol. Cell Biol. Lipids 2015, 1861, 784–792.
  120. Vykoukal, J.; Fahrmann, J.F.; Gregg, J.R.; Tang, Z.; Basourakos, S.; Irajizad, E.; Park, S.; Yang, G.; Creighton, C.J.; Fleury, A.; et al. Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer. Nat. Commun. 2020, 11, 1–16.
  121. Separovic, D.; Shields, A.F.; Philip, P.A.; Bielawski, J.; Bielawska, A.; Pierce, J.S.; Tarca, A.L. Altered Levels of Serum Ceramide, Sphingosine and Sphingomyelin Are Associated with Colorectal Cancer: A Retrospective Pilot Study. Anticancer Res. 2017, 37, 1213–1218.
  122. Modrak, D.E.; Cardillo, T.M.; Newsome, G.A.; Goldenberg, D.M.; Gold, D.V. Synergistic Interaction between Sphingomyelin and Gemcitabine Potentiates Ceramide-Mediated Apoptosis in Pancreatic Cancer. Cancer Res. 2004, 64, 8405–8410.
  123. Rozhkova, A.V.; Zinovyeva, M.V.; Sass, A.V.; Zborovskaya, I.B.; Limborska, S.A.; Dergunova, L.V. Expression of sphingomyelin synthase 1 (SGMS1) gene varies in human lung and esophagus cancer. Mol. Biol. 2014, 48, 340–346.
  124. Zheng, K.; Chen, Z.; Feng, H.; Chen, Y.; Zhang, C.; Yu, J.; Luo, Y.; Zhao, L.; Jiang, X.; Shi, F. Sphingomyelin synthase 2 promotes an aggressive breast cancer phenotype by disrupting the homoeostasis of ceramide and sphingomyelin. Cell Death Dis. 2019, 10, 1–11.
  125. Veldman, R.J.; Zerp, S.; Van Blitterswijk, W.J.; Verheij, M. N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br. J. Cancer 2004, 90, 917–925.
  126. Mazzei, J.C.; Zhou, H.; Brayfield, B.P.; Hontecillas, R.; Bassaganya-Riera, J.; Schmelz, E.M. Suppression of intestinal inflammation and inflammation-driven colon cancer in mice by dietary sphingomyelin: Importance of peroxisome proliferator-activated receptor γ expression. J. Nutr. Biochem. 2011, 22, 1160–1171.
  127. Modrak, D.E.; Leon, E.; Goldenberg, D.M.; Gold, D.V. Ceramide Regulates Gemcitabine-Induced Senescence and Apoptosis in Human Pancreatic Cancer Cell Lines. Mol. Cancer Res. 2009, 7, 890–896.
  128. Shakor, A.B.A.; Taniguchi, M.; Kitatani, K.; Hashimoto, M.; Asano, S.; Hayashi, A.; Nomura, K.; Bielawski, J.; Bielawska, A.; Watanabe, K.; et al. Sphingomyelin Synthase 1-generated Sphingomyelin Plays an Important Role in Transferrin Trafficking and Cell Proliferation. J. Biol. Chem. 2011, 286, 36053–36062.
  129. Taniguchi, M.; Ueda, Y.; Matsushita, M.; Nagaya, S.; Hashizume, C.; Arai, K.; Kabayama, K.; Fukase, K.; Watanabe, K.; Wardhani, L.O.; et al. Deficiency of sphingomyelin synthase 2 prolongs survival by the inhibition of lymphoma infiltration through ICAM-1 reduction. FASEB J. 2020, 34, 3838–3854.
  130. Rothwell, J.A.; Murphy, N.; Bešević, J.; Kliemann, N.; Jenab, M.; Ferrari, P.; Achaintre, D.; Gicquiau, A.; Vozar, B.; Scalbert, A.; et al. Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort. Clin. Gastroenterol. Hepatol. 2021, 20, e1061–e1082.
  131. To, N.B.; Nguyen, Y.T.-K.; Moon, J.Y.; Ediriweera, M.K.; Cho, S.K. Pentadecanoic Acid, an Odd-Chain Fatty Acid, Suppresses the Stemness of MCF-7/SC Human Breast Cancer Stem-Like Cells through JAK2/STAT3 Signaling. Nutrients 2020, 12, 1663.
  132. Ediriweera, M.K.; To, N.B.; Lim, Y.; Cho, S.K. Odd-chain fatty acids as novel histone deacetylase 6 (HDAC6) inhibitors. Biochimie 2021, 186, 147–156.
  133. Matejcic, M.; Lesueur, F.; Biessy, C.; Renault, A.-L.; Mebirouk, N.; Yammine, S.; Keski-Rahkonen, P.; Li, K.; Hémon, B.; Weiderpass, E.; et al. Circulating plasma phospholipid fatty acids and risk of pancreatic cancer in a large European cohort. Int. J. Cancer 2018, 143, 2437–2448.
  134. Hori, A.; Ishida, F.; Nakazawa, H.; Yamaura, M.; Morita, S.; Uehara, T.; Honda, T.; Hidaka, H. Serum sphingomyelin species profile is altered in hematologic malignancies. Clin. Chim. Acta 2021, 514, 29–33.
  135. Barré, F.P.; Claes, B.S.; Dewez, F.; Peutz-Kootstra, C.J.; Munch-Petersen, H.F.; Grønbæk, K.; Lund, A.H.; Heeren, R.M.; Côme, C.R.M.; Cillero-Pastor, B. Specific Lipid and Metabolic Profiles of R-CHOP-Resistant Diffuse Large B-Cell Lymphoma Elucidated by Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging and in Vivo Imaging. Anal. Chem. 2018, 90, 14198–14206.
  136. Kölzer, M.; Arenz, C.; Ferlinz, K.; Werth, N.; Schulze, H.; Klingenstein, R.; Sandhoff, K. Phosphatidylinositol-3,5-Bisphosphate Is a Potent and Selective Inhibitor of Acid Sphingomyelinase. Biol. Chem. 2003, 384, 1293–1298.
  137. Cumin, C.; Huang, Y.-L.; Everest-Dass, A.; Jacob, F. Deciphering the Importance of Glycosphingolipids on Cellular and Molecular Mechanisms Associated with Epithelial-to-Mesenchymal Transition in Cancer. Biomolecules 2021, 11, 62.
  138. Boscher, C.; Zheng, Y.Z.; Lakshminarayan, R.; Johannes, L.; Dennis, J.W.; Foster, L.J.; Nabi, I.R. Galectin-3 Protein Regulates Mobility of N-cadherin and GM1 Ganglioside at Cell-Cell Junctions of Mammary Carcinoma Cells. J. Biol. Chem. 2012, 287, 32940–32952.
  139. Van Slambrouck, S.; Groux-Degroote, S.; Krzewinski-Recchi, M.-A.; Cazet, A.; Delannoy, P.; Steelant, W.F.A. Carbohydrate-to-carbohydrate interactions between α2,3-linked sialic acids on α2 integrin subunits and asialo-GM1 underlie the bone metastatic behaviour of LNCAP-derivative C4-2B prostate cancer cells. Biosci. Rep. 2014, 34, 546–557.
  140. Talabnin, K.; Talabnin, C.; Kumagai, T.; Sutatum, N.; Khiaowichit, J.; Dechsukhum, C.; Ishihara, M.; Azadi, P.; Sripa, B. Ganglioside GM2: A potential biomarker for cholangiocarcinoma. J. Int. Med Res. 2020, 48, 0300060520903216.
  141. Ruckhäberle, E.; Karn, T.; Rody, A.; Hanker, L.; Gätje, R.; Metzler, D.; Holtrich, U.; Kaufmann, M. Gene expression of ceramide kinase, galactosyl ceramide synthase and ganglioside GD3 synthase is associated with prognosis in breast cancer. J. Cancer Res. Clin. Oncol. 2009, 135, 1005–1013.
  142. Dobrenkov, K.; Ostrovnaya, I.; Gu, J.; Cheung, I.Y.; Cheung, N.-K.V. Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults. Pediatr. Blood Cancer 2016, 63, 1780–1785.
  143. Tanaka, K.; Mikami, M.; Aoki, D.; Kiguchi, K.; Ishiwata, I.; Iwamori, M. Expression of sulfatide and sulfated lactosylceramide among histological types of human ovarian carcinomas. Hum. Cell 2015, 28, 37–43.
  144. Liu, Y.; Chen, Y.; Momin, A.; Shaner, R.; Wang, E.; Bowen, N.J.; Matyunina, L.V.; Walker, L.D.; McDonald, J.F.; Sullards, M.C.; et al. Elevation of sulfatides in ovarian cancer: An integrated transcriptomic and lipidomic analysis including tissue-imaging mass spectrometry. Mol. Cancer 2010, 9, 186.
  145. Moghimi, B.; Muthugounder, S.; Jambon, S.; Tibbetts, R.; Hung, L.; Bassiri, H.; Hogarty, M.D.; Barrett, D.M.; Shimada, H.; Asgharzadeh, S. Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma. Nat. Commun. 2021, 12, 1–15.
  146. Charan, M.; Dravid, P.; Cam, M.; Audino, A.; Gross, A.C.; Arnold, M.A.; Roberts, R.D.; Cripe, T.P.; Pertsemlidis, A.; Houghton, P.J.; et al. GD2-directed CAR-T cells in combination with HGF-targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma. Int. J. Cancer 2019, 146, 3184–3195.
  147. Andersch, L.; Radke, J.; Klaus, A.; Schwiebert, S.; Winkler, A.; Schumann, E.; Grunewald, L.; Zirngibl, F.; Flemmig, C.; Jensen, M.C.; et al. CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing. BMC Cancer 2019, 19, 1–17.
  148. Huang, C.S.; Yu, A.L.; Tseng, L.M.; Chow, L.W.C.; Hou, M.F.; Hurvitz, S.A.; Schwab, R.B.; Murray, J.L.; Chang, H.K.; Chang, H.T.; et al. Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: Phase II randomized, placebo-controlled study. J. Immunother. Cancer 2020, 8, e000342.
  149. Giussani, P.; Prinetti, A.; Tringali, C. The Role of Sphingolipids in Cancer Immunotherapy. Int. J. Mol. Sci. 2021, 22, 6492.
  150. Yu, J.; Hung, J.T.; Wang, S.H.; Cheng, J.Y.; Yu, A.L. Targeting glycosphingolipids for cancer immunotherapy. FEBS Lett. 2020, 594, 3602–3618.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback