Sphingosine Kinase 1 in Breast Cancer Stem Cells: History
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Subjects: Biochemistry & Molecular Biology
Contributor:
Ling-Wei Hii
,
Felicia Fei-Lei Chung
,
Chun Wai Mai
,
Zong Yang Yee
,
Hong Hao Chan
,
Vijay Joseph Raja
,
Noah Elias Dephoure
,
Nigel J. Pyne
,
Susan Pyne
,
Chee-Onn Leong

Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to effcient tumor treatment. In our research article published in Cells (https://doi.org/10.3390/cells9040886), we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming effciency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.

  • cancer stem cells
  • sphingosine kinase
  • STAT1
  • mammospheres
  • drug synergism
  • sphingolipids

Breast cancer stem cells (CSCs) represent a subset of cancer cells with the capabilities of self-renewal and differentiation [1] . Although several signaling pathways (such as STAT3 [2], Wnt/β-Catenin[3], Notch [4], Hedgehog [5], and NFκB [6]) have been implicated in regulating the growth and survival of breast CSCs, designing selective CSC-targeted strategies using these pathways remains a challenge as these pathways also share common functional roles in the maintenance of normal stem cells [7].

Sphingosine kinase (SPHK) catalyses the ATP-dependent phosphorylation of sphingosine to form sphingosine 1-phosphate (S1P), which acts as an intracellular second messenger and extracellular ligand for specific receptors [8]. S1P can be released through specific transporters to act as a ligand for the family of G protein-coupled S1P receptors 1 to 5 (S1P1 to S1P5) and regulates a wide range of biological effects including transformation and cancer cell survival [9]. S1P levels are tightly regulated by the balance between synthesis by SPHK, reversible conversion to sphingosine by specific S1P phosphatases (SPP1 and SPP2), and degradation by S1P lyase [10]. In contrast to S1P, which is associated with growth and survival, its precursors, sphingosine and ceramide, are associated with cell growth arrest and apoptosis [11]. According to the sphingolipid rheostat model, the balance between these interconvertible sphingolipids, ceramide, sphingosine, and S1P, regulates cellular growth and survival in response to cellular and environmental stimuli [12][13]. Thus, SPHK is a critical regulator of this rheostat, as it produces the pro-growth and anti-apoptotic S1P and also reduces levels of pro-apoptotic ceramide and sphingosine [11][14][15][16][17][18]. Thus, the inhibition of SPHK is likely to have an anti-cancer effect by producing apoptotic ceramide/sphingosine.

There are two isoforms of sphingosine kinase called SPHK1 and SPHK2. Several studies have indicated that increased SPHK1 activity promotes cancer cell growth, metastasis, and inhibits apoptosis [9][10][11][19][20][21]. Indeed, high expression of SPHK1 in tumors is associated with worse prognosis and overall outcomes in breast cancer patients [21][22][23][24][25][26][27][28]. In addition, overexpression of SPHK1 in breast cancer cells was reported to increase breast CSCs and the tumorigenicity of tumors in nude mice via S1P binding to S1P3 and down-stream stimulation of Notch and p38 MAPK signaling [29]. Furthermore, benzyl butyl phthalate, a carcinogen that has been shown to induce SPHK1 expression through activation of the aryl hydrocarbon receptor (AhR), was recently shown to enhance the formation of metastasis-initiating breast CSCs, suggesting a role of SPHK1 in breast CSCs [30].

Using a kinome-wide shRNA library screen, we previously identified that SPHK1 is required for breast cancer cell survival [31]. However, whether SPHK1 is required for the survival of breast CSCs remains unknown. Hence, this study sought to investigate whether SPHK1 regulates the survival of breast CSCs, the underlying mechanism of this protection, and whether there are any substantive differences with its role in non-CSCs. In this regard, we demonstrate herein that SPHK1 expression is increased in breast CSCs compared with non-CSCs and is involved in regulating the survival of breast CSCs and non-CSCs through repression of the tumor suppressor function of STAT1 [32]. Importantly, selective inhibition of SPHK1 enhances doxorubicin sensitivity in breast CSCs and non-CSCs [32]. Overall, our results implicate SPHK1 as a potential target for the treatment of refractory breast cancers by targeting both breast CSCs and non-CSCs [32].

Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1

 

 

This entry is adapted from the peer-reviewed paper 10.3390/cells9040886

References

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  21. Jaclyn S. Long; Joanne Edwards; Carol Watson; Sian Tovey; Kirsty M. Mair; Rachel Schiff; Viswanathan Natarajan; Susan Pyne; Susan Pyne; Sphingosine Kinase 1 Induces Tolerance to Human Epidermal Growth Factor Receptor 2 and Prevents Formation of a Migratory Phenotype in Response to Sphingosine 1-Phosphate in Estrogen Receptor-Positive Breast Cancer Cells. Molecular and Cellular Biology 2010, 30, 3827-3841, 10.1128/mcb.01133-09.
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  26. Carol Watson; Jaclyn S. Long; Clare Orange; Claire L. Tannahill; Elizabeth Mallon; Liane McGlynn; Susan Pyne; Susan Pyne; Joanne Edwards; High Expression of Sphingosine 1-Phosphate Receptors, S1P1 and S1P3, Sphingosine Kinase 1, and Extracellular Signal-Regulated Kinase-1/2 Is Associated with Development of Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Patients. The American Journal of Pathology 2010, 177, 2205-2215, 10.2353/ajpath.2010.100220.
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  31. Kai Hung Tiong; Boon Shing Tan; Heng Lungh Choo; Felicia Fei-Lei Chung; Ling-Wei Hii; Si Hoey Tan; Nelson Tze Woei Khor; Shew Fung Wong; Sze-Jia See; Yuen-Fen Tan; et al. Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival. Oncotarget 2016, 7, 57633-57650, 10.18632/oncotarget.9328.
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