Apoptosis Inhibitor 5 and Cancer: Comparison
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Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Jean-Luc Poyet.

Apoptosis, or programmed cell death, is a fundamental process that maintains tissue homeostasis, eliminates damaged or infected cells, and plays a crucial role in various biological phenomena. The deregulation of apoptosis is involved in many human diseases, including cancer. One of the emerging players in the intricate regulatory network of apoptosis is apoptosis inhibitor 5 (API5), also called AAC-11 (anti-apoptosis clone 11) or FIF (fibroblast growth factor-2 interacting factor). While it may not have yet the same level of notoriety as some other cancer-associated proteins, API5 has garnered increasing attention in the cancer field in recent years, as elevated API5 levels are often associated with aggressive tumor behavior, resistance to therapy, and poor patient prognosis.

  • apoptosis inhibitor 5
  • apoptosis
  • cancer

1. Introduction

Apoptosis is a highly regulated form of programmed cell death that plays a crucial role in various physiological and pathological conditions, including development, tissue homeostasis, and the removal of damaged or unnecessary cells [1,2,3,4][1][2][3][4]. It is now well established that defects in the apoptotic pathways are closely related to both oncogenesis and cancer treatments resistance [5,6,7,8][5][6][7][8]. Understanding the molecular mechanisms regulating apoptosis is therefore of crucial importance for the identification of specific targets for anticancer therapies. Apoptosis execution relies on the highly regulated activation of a group of cysteine proteases called caspases that specifically cleave a series of substrates, resulting in cell death [9,10,11][9][10][11]. Caspases are synthesized as inert zymogens that are activated through two distinct, but interconnected, pathways, called the intrinsic or extrinsic pathways, in which apoptotic stimuli trigger the activation of the so-called initiator caspases (such as caspase-2, -8, -9, and -10) which, in turn, proteolytically cleave and activate effector (or executioner) caspases (caspase-3, -6, and -7) [12,13][12][13]. When activated, the effector caspases specifically cleave a broad spectrum of cellular targets, ultimately leading to cell death.
The extrinsic pathway is initiated by the activation of death receptors, upon binding of their cognate ligands and subsequent recruitment at the level of the cytoplasmic region of the death receptors of death domain-containing adaptor proteins [2]. This results in the formation of a death-inducing signaling complex (DISC), which can in turn recruit and activate caspase-8 via oligomerization. Death receptor-mediated apoptosis can be inhibited by a proteolytically inactive homolog of caspase-8, called cellular FLICE inhibitory protein (cFLIP), which can be recruited to the DISC, forming a proteolytically inactive heterodimer with caspase-8 [14].
The intrinsic pathway, also known as the mitochondrial pathway, proceeds through the induction of the mitochondrial outer membrane permeabilization (MOMP) and the subsequent release in the cytoplasm of numerous proapoptotic mitochondrial constituents [15]. Among these, cytochrome c promotes the oligomerization of apoptotic protease-activating factor-1 (APAF-1), triggering the formation of the apoptosome and dimerization-induced activation of caspase-9 [16]. The intrinsic pathway is intricately regulated by pro- and anti-apoptotic B-cell lymphoma-2 (Bcl-2) family members, which consist of evolutionarily conserved proteins that share at least one Bcl-2 homology (BH) domain [17].
Although the connection between the number of genetic mutations and cancer is complex, the tumorigenesis process relies on both the activation of oncogenes that stimulate cancer cells proliferation and survival, as well as the inactivation of tumor suppressor genes that hold cellular proliferation in check [18]. To date, a wide variety of oncogenes and tumor suppressor genes involved in the regulation of pro- or anti-apoptotic signals have been discovered. Variations in the expression of these genes, or their mutation, can contribute to tumor initiation, progression or resistance to treatment. Consequently, a number of therapeutic approaches have been developed to overcome cell death resistance through the pharmacological manipulation of various apoptosis signaling networks. Current main therapeutic strategies include either inhibiting antiapoptotic regulators or stimulating proapoptotic factors [19,20][19][20]. For instance, a number of inhibitors of antiapoptotic Bcl-2 family members, which are known to be overexpressed in numerous cancers, are now used in clinics. These include the Bcl2-selective BH3-mimetic Venetoclax [21], which is currently used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, or acute myeloid leukemia, or the myeloid cell leukemia-1 (Mcl-1) inhibitors S63845, AMG-176, and AZD5991 [22,23,24][22][23][24].
Among the cell death regulators is API5 (apoptosis inhibitor-5), also known as AAC-11 (anti-apoptosis clone 11 or FIF (fibroblast growth factor-2 interacting factor)), a 55 kDa nuclear scaffold protein initially discovered as a negative regulator of apoptosis upon nutritional stress conditions [25]. API5 has emerged as a key player in the context of cancer as its overexpression has been associated with aggressive tumor behavior, resistance to treatment, and poor prognosis [26,27,28,29,30,31,32,33,34,35][26][27][28][29][30][31][32][33][34][35]. Furthermore, recent observations indicate that API5 influence extends far beyond apoptosis regulation, making this intriguing protein a versatile regulator of cell fate with diverse functions ranging from anti-apoptosis to metastasis, cell cycle control, mRNA export, and TLR4-dependent activation and maturation of antigen presenting cells. API5’s intricate involvement in these critical cellular processes underscores its significance in both health and disease, particularly in cancer biology. 

2. Apoptosis Inhibitor 5 and Cancer

2.1. API5 Expression and Prognosis Value

An expression analysis of API5 revealed an ubiquitous but varying expression of API5 in cancers. Of note, the human API5 gene is located in chromosomal segment 11p12-13, in a region that is amplified in a number of cancers [111,112,113,114][36][37][38][39]. API5 has been shown to be upregulated in various cancers, such as breast cancer, colorectal cancer, cervical cancer, NSCLC, or B-cell chronic lymphoid leukemia [26,28,29,30,31,32,33,35,86,115,116][26][28][29][30][31][32][33][35][40][41][42]. This expression appears to be clinically relevant as it is associated with poor overall and disease-free survival as well as resistance to treatment, suggesting a potential role for API5 as a prognosis and survival marker [26,28,29,30,31,32,33,35,86][26][28][29][30][31][32][33][35][40]. In line with this hypothesis, Cho and colleagues have shown that API5 expression levels gradually increased during the normal-to-tumor transition of cervical carcinoma [28]. As API5 overexpression has been linked to cancer cell proliferation (see above) and survival (see below), one might envision that API5 could contribute to the development and progression of cancer.

2.2. API5’s Role on Cancer Metastasis, Immune Response, and Survival

The widespread and high expression of API5 in tumors suggests that API5 contributes to human malignancy. Interestingly, a recent study has shown that overexpression of API5 in breast epithelial cells induces a partial epithelial–mesenchymal transition (EMT)-like phenotype [86][40]. EMT is a differentiation process through which transformed epithelial cells gain the ability to invade and disseminate [117][43]. In line with this hypothesis, API5 expression has been demonstrated to contribute to tumor invasion and metastases in various cancer settings [26,29,34,86][26][29][34][40]. One important step in invasion is the remodeling and disassembly of the extracellular matrix and its constituents through enzymes such as matrix metalloproteinases (MMPs) [118][44]. MMPs are structurally related, zinc-dependent endopeptidases that have been linked to a wide variety of pathological states, including carcinogenesis, and elevated levels of MMPs correlate with unfavorable prognosis in multiple cancers [119][45]. An API5-forced expression increases levels of MMP-2 as well as membrane type 1 matrix metalloproteinase (MT1-MMP), with concomitant downregulation of the tissue inhibitor of MMP (TIMP-2) [29]. While the mechanism by which API5 regulates MMP-2 and MT1-MMP expression are not clear yet, API5 expression has been linked to the upregulation of the transcriptional coactivator β-catenin, which is well known to possess a crucial role in cell invasion and to regulate MMPs expression [120][46]. Furthermore, using other tumor settings, Song and colleagues demonstrated that API5 enhanced MMP-9 expression through an ERK-dependent regulation of activator protein 1 (AP-1) [34]. Therefore, it is possible that API5 contributes to cancer metastasis through β-catenin- and ERK-mediated MMPs expression (Figure 1).
Figure 1. Metastasis regulation by API5. API5 increases tumor cell metastasis via upregulation of MMP-2, MMP-9, and MT1-MMP expression and downregulation of TIMP-2 levels.
Another mechanism by which API5 contributes to tumor progression is through the induction of tumor immune escape. Indeed, in a very interesting study, the group led by Tae Woo Kim demonstrated that API5 plays key roles in both tumor progression and immunity [31]. Using different murine cancer models, Kim and colleagues showed that API5 could render tumor cells resistant to immune-mediated cytotoxicity, through the inhibition of tumor-specific T-cell-mediated apoptosis [31]. Mechanistically, API5 hinders T-cell-triggered apoptosis of cancerous cells by the upregulation of FGF-2 and subsequent activation of the FGFR1–PKCδ–ERK pathway, resulting in the ubiquitin-dependent degradation of the BH3-only protein BIM (Figure 2). Although these observations need to be confirmed using primary samples, they fit well with previous data indicating that cancer cells with high levels of AKT/ERK exhibit suppressed BIM expression [121[47][48],122], and they identify API5 as an immune-related prognostic biomarker. Therapeutic targeting of API5 could therefore represent a potential treatment option for cancer through tumor immune escape.
Figure 2. Anti-apoptotic functions of API5. API5 regulation of apoptosis takes place at four levels: (1) API5 inhibits E2F1-induced apoptosis. (2) API5 inhibits Acinus-induced apoptotic DNA fragmentation. (3) API5 inhibits caspase-2 activation. (4) API5 upregulates FGF2/FGFR1 signaling, leading to BIM degradation. Of note, API5-mediated activation of FGFR1 signaling, which triggers proteasome-dependent degradation of BIM, is also involved in the chemo- and immune-resistance of cancer cells.
Finally, a substantial number of studies have shown that API5, which was initially identified for its antiapoptotic function, is critically involved in tumor survival and resistance to chemotherapeutic drugs. Morris and colleagues initially noted that the depletion of API5 was specifically lethal to tumor cells with deregulated E2F1 [39][49]. Shortly after, a crucial role for API5 in tumor cells’ sensitivity to anticancer drug was demonstrated by different groups. Indeed, the silencing of API5 in various cell lines sharply increased tumor cells’ sensitivity to chemotherapeutic drugs such as etoposide, camptothecin, or cisplatin, whereas API5-forced expression endowed cancer cells with enhanced resistance to these agents [26,65,123][26][50][51]. Although more research is needed to completely decipher the mechanisms at play, API5-induced resistance to anticancer drugs has been shown to stem from its activation of the FGFR1 signaling, which triggers the ERK-mediated degradation of the proapoptotic protein BIM, as well as the inhibition of caspase-2 and apoptotic DNA fragmentation [26,51,65,123][26][50][51][52] (Figure 2). Recently, API5 silencing has been linked to a sharp increase in cell death of caspase 9−/− Jurkat cells treated with ABT-263, a potent and selective inhibitor of Bcl-2 and Bcl-xL [124][53]. Interestingly, ABT-263 is known to synergize with chemotherapies inducing DNA damage [125,126][54][55]. As the silencing of API5 promotes ABT-263-induced DNA damage [124][53], it is possible that API5 could function as a regulator of the DNA repair machinery, as its association with the chromatin remodeler ALC1 (amplified in liver cancer 1), which plays a key role in DNA repair, suggests [49][56]. In line with this hypothesis, API5 has been shown to be upregulated by UV irradiation of primary liver cells, and an increased expression of API5 protects primary liver cells from UV-induced apoptosis and to increase glioblastoma cells to radioresistance [127,128,129][57][58][59].
Combined, these data demonstrate a crucial role for API5 in cancer cell development and progression, providing a rationale for the therapeutic targeting of API5 for cancer treatment.

2.3. Targeting API5 as a Therapeutic Approach

Cancer is a consequence of multiple deregulated processes that endow tumor cells with certain traits which were described as “Hallmarks of Cancer” by Hanahan and Weinberg two decades ago [130][60]. Numerous new potential cancer targets have been identified over the last few years, and survival pathways, angiogenesis, DNA damage response (DDR), senescence pathways or the immune system, for instance, are important types of targets for the development of anticancer drugs. Clearly, given the above-described functions of API5, targeting this intriguing protein could be of great interest for cancer treatment. Among the different opportunities to indirectly or directly target proteins are their inhibition at the expression level, their inhibition through physical degradation or their inhibition at the protein/protein interaction level.
The downregulation of API5 expression has been achieved so far by means of RNA interference (RNAi), short hairpin RNAs (shRNAs), or microRNA (miRNA), and all these approaches have demonstrated interesting potentialities as they have resulted in cancer cells death, increased sensitivity to anticancer agents or immune-mediated cytotoxicity or inhibition of metastasis potential (see above). Therefore, RNA-based therapeutics approaches for API5 expression targeting could open novel possibilities for cancer treatment. However, critical challenges in applying these RNA therapies, related to pharmacodynamics and pharmacokinetics as well as immunogenicity issues, have hindered the clinical progress of RNA-based drugs [131][61]. Nonetheless, a substantial number of RNA-based therapeutics are currently under clinical investigation for various diseases, including cancers, and several RNA-based medications have been approved for clinical use [132][62]. Therefore, further research on RNA-based therapeutics for API5 targeting might lead to more RNA-based therapeutics for cancer treatment.
Direct API5 degradation is another therapeutic option. API5 stability has been demonstrated to be regulated via acetylation at lysine 251 (K251) by the histone acetyltransferase p300, which leads to an increase inAPI5 stability, whereas deacetylation by the histone deacetylase 1 HDAC1 reduces API5 levels [53][63]. Consequently, chemical inhibition of p300 resulted in decreased API5 levels, affecting its functions in cell cycle [53][63]. Interestingly, the expression of an acetylation-deficient mutant of API5 (K251A) did not protect tumor cells from apoptosis induced by serum deprivation [40][64]. Furthermore, tumor cells expressing API5 K251A in an API5 knockdown background could not survive while in culture [53][63]. Therefore, one can envision that the use of p300 inhibitors could constitute an interesting therapeutic option for the induction of the direct degradation of API5. As a matter of fact, the development of p300 inhibitors has attracted great attention in recent years due to its potential therapeutic value in the treatment of cancers [133,134][65][66]. Consequently, the steady-state API5 acetylation–methylation equilibrium, which functions as a molecular rheostat governing API5 stability and antiapoptotic properties, might be amenable to therapeutic exploitation as an anti-cancer strategy.
Finaly, the inhibition of API5 interactions with its partner proteins is another approach to target its biological functions. API5 interacts with several apoptosis-related proteins, and this complex-forming ability—probably favored by its elongated 3D structure [40][64]—appears to be essential for API5 to fulfill its antiapoptotic or metastatic functions [25,34,48,49,65][25][34][50][56][67]. Among its different domains, API5 contains several protein–protein interaction modules, such as HEAT and ARM repeat or the heptad leucine repeat region (Figure 3). Researchers has shown that the heptad leucine repeat region of API5 mediates its interaction with several of its partners, such as Acinus and the kinase p21-activated kinase 1 (PAK1) [54,65][50][68]. Moreover, mutations of conserved residues (leucines 384 and 391 or arginine 382) in this domain abrogate API5 biological functions and prevent its interaction with its molecular partners [25,34,48,54,65,134][25][34][50][66][67][68]. This indicates that the heptad leucine repeat region of API5 could constitute a therapeutic target for anti-cancer drugs. Researchers have constructed two API5-derived cell-permeable peptides, called RT53 and RT39, that comprise portions of the heptad leucine repeat region of API5 fused to a cell-penetrating sequence [54,65][50][68]. Both peptides acted as decoys and were able to prevent interaction between API5 and Acinus or PAK1 [54,65][50][68]. Moreover, the peptides demonstrated potent pro-apoptotic activity and synergy with anticancer drugs, as well as anti-migration potential, on multiple cancer cell lines as well as primary cutaneous T-cell lymphoma (Sézary syndrome) cells, thus phenocopying the consequences of API5 silencing [54,65,135,136,137][50][68][69][70][71]. The peptides also demonstrated in vivo efficacy as single agents in murine models of melanoma, breast cancer, acute promyelocytic leukemia, and Sézary syndrome, with very favorable half-lives in mice [27,54,65,135,136,137,138,139][27][50][68][69][70][71][72][73]. Structurally, RT53 and RT39 adopt a helical conformation, with an N-terminal stretch of arginine and lysine residues followed by a hydrophobic region, making them amphipathic and membrane active, similarly to other know membranolytic peptides [140][74]. Therefore, while sparing normal cells, the RT53 and RT39 peptides also possess oncolytic properties [54,135,136,137,139][68][69][70][71][73]. Mechanistically, RT39 retention in the membrane of Sézary cells is dependent on binding to PAK1 at the level of the plasma membrane, where PAK1 is strongly expressed [54,135][68][69]. Interestingly, oncolysis mediated by RT53 exhibited the hallmarks of immunogenic cell death, and vaccines consisting of APL or melanoma cells exposed in vitro to RT53 induced prophylactic and therapeutic protection in syngeneic murine models [136,137][70][71]. Therefore, RT53 and RT39 peptides’ anti-cancer action stems from both their ability to prevent API5 biological functions, through protein–protein interaction inhibition, and through their oncolytic properties.
Figure 3. Domain organization of API5. The LxxLL motif, the acetylation site (K251), the SUMOylation site (K404), the heptad leucine repeat (HLR), and the nuclear localization domain (NLS) are shown. Numbers indicate amino acids positions.
Recently, the crystal structure of the API5–FGF-2 complex has been solved, allowing for the determination of the precise domains of the proteins involved in their interaction [47][75]. Based on this knowledge, Bong and colleagues have developed lentiviruses expressing a peptide composed of API5 residues 183–191, a domain involved in API5 interaction with FGF-2. Interestingly, the lentivirus-mediated expression of the API5-derived peptide in HeLa cells abrogated API5–FGF-2 interaction and reduced the nuclear export of bulk RNA, which is dependent on the API5–FGF-2 complex [47][75]. While it remains to be determined whether this novel API5-derived peptide exhibits anticancer effect or synergizes with anticancer drugs, these data support the testing of API5-derived peptides for cancer treatment.

References

  1. Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. Apoptosis: Mechanisms and relevance in cancer. Ann. Hematol. 2005, 84, 627–639.
  2. Fuchs, Y.; Steller, H. Live to die another way: Modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 2015, 16, 329–344.
  3. Geske, F.J.; Gerschenson, L.E. The biology of apoptosis. Hum. Pathol. 2001, 32, 1029–1038.
  4. Meier, P.; Vousden, K.H. Lucifer’s labyrinth—Ten years of path finding in cell death. Mol. Cell 2007, 28, 746–754.
  5. Igney, F.H.; Krammer, P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer 2002, 2, 277–288.
  6. Wong, R.S. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011, 30, 87.
  7. Pfeffer, C.M.; Singh, A.T.K. Apoptosis: A Target for Anticancer Therapy. Int. J. Mol. Sci. 2018, 19, 448.
  8. Tuveson, D.; Hanahan, D. Translational medicine: Cancer lessons from mice to humans. Nature 2011, 471, 316–317.
  9. Green, D.R. Caspases and Their Substrates. Cold Spring Harb. Perspect. Biol. 2022, 14, a041012.
  10. Lamkanfi, M.; Festjens, N.; Declercq, W.; Berghe, T.V.; Vandenabeele, P. Caspases in cell survival, proliferation and differentiation. Cell Death Differ. 2007, 14, 44–55.
  11. Thornberry, N.A.; Lazebnik, Y. Caspases: Enemies within. Science 1998, 281, 1312–1316.
  12. Li, J.; Yuan, J. Caspases in apoptosis and beyond. Oncogene 2008, 27, 6194–6206.
  13. Shi, Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol. Cell 2002, 9, 459–470.
  14. Krueger, A.; Schmitz, I.; Baumann, S.; Krammer, P.H.; Kirchhoff, S. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex. J. Biol. Chem. 2001, 276, 20633–20640.
  15. Wang, Z.; Figueiredo-Pereira, C.; Oudot, C.; Vieira, H.L.A.; Brenner, C. Mitochondrion: A Common Organelle for Distinct Cell Deaths? Int. Rev. Cell Mol. Biol. 2017, 331, 245–287.
  16. Bao, Q.; Shi, Y. Apoptosome: A platform for the activation of initiator caspases. Cell Death Differ. 2007, 14, 56–65.
  17. Levine, B.; Sinha, S.; Kroemer, G. Bcl-2 family members: Dual regulators of apoptosis and autophagy. Autophagy 2008, 4, 600–606.
  18. Kontomanolis, E.N.; Koutras, A.; Syllaios, A.; Schizas, D.; Mastoraki, A.; Garmpis, N.; Diakosavvas, M.; Angelou, K.; Tsatsaris, G.; Pagkalos, A.; et al. Role of Oncogenes and Tumor-suppressor Genes in Carcinogenesis: A Review. Anticancer. Res. 2020, 40, 6009–6015.
  19. Plati, J.; Bucur, O.; Khosravi-Far, R. Apoptotic cell signaling in cancer progression and therapy. Integr. Biol. 2011, 3, 279–296.
  20. Reed, J.C. Apoptosis-targeted therapies for cancer. Cancer Cell 2003, 3, 17–22.
  21. Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013, 19, 202–208.
  22. Kotschy, A.; Szlavik, Z.; Murray, J.; Davidson, J.; Maragno, A.L.; Le Toumelin-Braizat, G.; Chanrion, M.; Kelly, G.L.; Gong, J.-N.; Moujalled, D.M.; et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 2016, 538, 477–482.
  23. Caenepeel, S.; Brown, S.P.; Belmontes, B.; Moody, G.; Keegan, K.S.; Chui, D.; Whittington, D.A.; Huang, X.; Poppe, L.; Cheng, A.C.; et al. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies. Cancer Discov. 2018, 8, 1582–1597.
  24. Tron, A.E.; Belmonte, M.A.; Adam, A.; Aquila, B.M.; Boise, L.H.; Chiarparin, E.; Cidado, J.; Embrey, K.J.; Gangl, E.; Gibbons, F.D.; et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat. Commun. 2018, 9, 5341.
  25. Tewari, M.; Yu, M.; Ross, B.; Dean, C.; Giordano, A.; Rubin, R. AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal. Cancer Res. 1997, 57, 4063–4069.
  26. Basset, C.; Bonnet-Magnaval, F.; Navarro, M.G.-J.; Touriol, C.; Courtade, M.; Prats, H.; Garmy-Susini, B.; Lacazette, E. Api5 a new cofactor of estrogen receptor alpha involved in breast cancer outcome. Oncotarget 2017, 8, 52511–52526.
  27. Bousquet, G.; Feugeas, J.-P.; Gu, Y.; Leboeuf, C.; El Bouchtaoui, M.; Lu, H.; Espié, M.; Janin, A.; Di Benedetto, M. High expression of apoptosis protein (Api-5) in chemoresistant triple-negative breast cancers: An innovative target. Oncotarget 2019, 10, 6577–6588.
  28. Cho, H.; Chung, J.-Y.; Song, K.-H.; Noh, K.H.; Kim, B.W.; Chung, E.J.; Ylaya, K.; Kim, J.H.; Kim, T.W.; Hewitt, S.M.; et al. Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer. BMC Cancer 2014, 14, 545.
  29. Kim, J.W.; Cho, H.S.; Kim, J.H.; Hur, S.Y.; Kim, T.E.; Lee, J.M.; Kim, I.K.; Namkoong, S.E. AAC-11 overexpression induces invasion and protects cervical cancer cells from apoptosis. Lab. Investig. 2000, 80, 587–594.
  30. Krejci, P.; Pejchalova, K.; Rosenbloom, B.E.; Rosenfelt, F.P.; Tran, E.L.; Laurell, H.; Wilcox, W.R. The antiapoptotic protein Api5 and its partner, high molecular weight FGF2, are up-regulated in B cell chronic lymphoid leukemia. J. Leukoc. Biol. 2007, 82, 1363–1364.
  31. Noh, K.H.; Kim, S.-H.; Kim, J.H.; Song, K.-H.; Lee, Y.-H.; Kang, T.H.; Han, H.D.; Sood, A.K.; Ng, J.; Kim, K.; et al. API5 confers tumoral immune escape through FGF2-dependent cell survival pathway. Cancer Res. 2014, 74, 3556–3566.
  32. Sasaki, H.; Moriyama, S.; Yukiue, H.; Kobayashi, Y.; Nakashima, Y.; Kaji, M.; Fukai, I.; Kiriyama, M.; Yamakawa, Y.; Fujii, Y. Expression of the antiapoptosis gene, AAC-11, as a prognosis marker in non-small cell lung cancer. Lung Cancer 2001, 34, 53–57.
  33. Song, K.H.; Cho, H.; Lee, H.J.; Oh, S.J.; Woo, S.R.; Hong, S.O.; Jang, H.S.; Noh, K.H.; Choi, C.H.; Chung, J.Y.; et al. API5 confers cancer stem cell-like properties through the FGF2-NANOG axis. Oncogenesis 2017, 6, e285.
  34. Song, K.H.; Kim, S.H.; Noh, K.H.; Bae, H.C.; Kim, J.H.; Lee, H.J.; Song, J.; Kang, T.H.; Kim, D.W.; Oh, S.J.; et al. Apoptosis Inhibitor 5 Increases Metastasis via Erk-mediated MMP expression. BMB Rep. 2015, 48, 330–335.
  35. Wang, Z.; Liu, H.; Liu, B.; Ma, W.; Xue, X.; Chen, J.; Zhou, Q. Gene expression levels of CSNK1A1 and AAC-11, but not NME1, in tumor tissues as prognostic factors in NSCLC patients. Med. Sci. Monit. 2010, 16, CR357-64.
  36. Carvalho, R.; Milne, A.N.; Polak, M.; Offerhaus, G.J.; Weterman, M.A. A novel region of amplification at 11p12-13 in gastric cancer, revealed by representational difference analysis, is associated with overexpression of CD44v6, especially in early-onset gastric carcinomas. Genes Chromosomes Cancer 2006, 45, 967–975.
  37. Klingbeil, P.; Natrajan, R.; Everitt, G.; Vatcheva, R.; Marchio, C.; Palacios, J.; Buerger, H.; Reis-Filho, J.S.; Isacke, C.M. CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res. Treat. 2010, 120, 95–109.
  38. Jarvinen, A.K.; Autio, R.; Kilpinen, S.; Saarela, M.; Leivo, I.; Grénman, R.; Mäkitie, A.A.; Monni, O. High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer 2008, 47, 500–509.
  39. Fukuda, Y.; Kurihara, N.; Imoto, I.; Yasui, K.; Yoshida, M.; Yanagihara, K.; Park, J.-G.; Nakamura, Y.; Inazawa, J. CD44 is a potential target of amplification within the 11p13 amplicon detected in gastric cancer cell lines. Genes Chromosomes Cancer 2000, 29, 315–324.
  40. Kuttanamkuzhi, A.; Panda, D.; Malaviya, R.; Gaidhani, G.; Lahiri, M. Altered expression of anti-apoptotic protein Api5 affects breast tumorigenesis. BMC Cancer 2023, 23, 374.
  41. Krejci, P.; Koci, L.; Chlebova, K.; Hyzdalova, M.; Hofmanova, J.; Jira, M.; Kysela, P.; Kozubik, A.; Kala, Z. Apoptosis inhibitor 5 (API-5; AAC-11; FIF) is upregulated in human carcinomas in vivo. Oncol. Lett. 2012, 3, 913–916.
  42. Ren, K.; Zhang, W.; Shi, Y.; Gong, J. Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway. Pathol. Oncol. Res. 2010, 16, 229–237.
  43. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  44. Curran, S.; Murray, G.I. Matrix metalloproteinases: Molecular aspects of their roles in tumour invasion and metastasis. Eur. J. Cancer 2000, 36, 1621–1630.
  45. Coussens, L.M.; Fingleton, B.; Matrisian, L.M. Matrix metalloproteinase inhibitors and cancer: Trials and tribulations. Science 2002, 295, 2387–2392.
  46. Wu, B.; Crampton, S.P.; Hughes, C.C. Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 2007, 26, 227–239.
  47. Costa, D.B.; Halmos, B.; Kumar, A.; Schumer, S.T.; Huberman, M.S.; Boggon, T.J.; Tenen, D.G.; Kobayashi, S. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 2007, 4, 1669–1679, discussion 1680.
  48. Hubner, A.; Barrett, T.; Flavell, R.A.; Davis, R.J. Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol. Cell 2008, 30, 415–425.
  49. Morris, E.J.; Michaud, W.A.; Ji, J.-Y.; Moon, N.-S.; Rocco, J.W.; Dyson, N.J. Functional identification of Api5 as a suppressor of E2F-dependent apoptosis in vivo. PLoS Genet. 2006, 2, e196.
  50. Rigou, P.; Piddubnyak, V.; Faye, A.; Rain, J.-C.; Michel, L.; Calvo, F.; Poyet, J.-L. The antiapoptotic protein AAC-11 interacts with and regulates Acinus-mediated DNA fragmentation. EMBO J. 2009, 28, 1576–1588.
  51. Janin, Y.L. Peptides with anticancer use or potential. Amino Acids 2003, 25, 1–40.
  52. Imre, G.; Berthelet, J.; Heering, J.; Kehrloesser, S.; Melzer, I.M.; Lee, B.I.; Thiede, B.; Dötsch, V.; Rajalingam, K. Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2. EMBO Rep. 2017, 18, 733–744.
  53. Chen, M.; Wang, L.; Li, M.; Budai, M.M.; Wang, J. Mitochondrion-Mediated Cell Death through Erk1-Alox5 Independent of Caspase-9 Signaling. Cells 2022, 11, 3053.
  54. Chen, Q.; Song, S.; Wei, S.; Liu, B.; Honjo, S.; Scott, A.; Jin, J.; Ma, L.; Zhu, H.; Skinner, H.D.; et al. ABT-263 induces apoptosis and synergizes with chemotherapy by targeting stemness pathways in esophageal cancer. Oncotarget 2015, 6, 25883–25896.
  55. Ho, C.J.; Ko, H.-J.; Liao, T.-S.; Zheng, X.-R.; Chou, P.-H.; Wang, L.-T.; Lin, R.-W.; Chen, C.-H.; Wang, C. Severe cellular stress activates apoptosis independently of p53 in osteosarcoma. Cell Death Discov. 2021, 7, 275.
  56. Ahel, D.; Hořejší, Z.; Wiechens, N.; Polo, S.E.; Garcia-Wilson, E.; Ahel, I.; Flynn, H.; Skehel, M.; West, S.C.; Jackson, S.P.; et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science 2009, 325, 1240–1243.
  57. Wang, Y.; Lee, A.T.C.; Ma, J.Z.I.; Wang, J.; Ren, J.; Yang, Y.; Tantoso, E.; Li, K.-B.; Ooi, L.L.P.J.; Tan, P.; et al. Profiling microRNA expression in hepatocellular carcinoma reveals microRNA-224 up-regulation and apoptosis inhibitor-5 as a microRNA-224-specific target. J. Biol. Chem. 2008, 283, 13205–13215.
  58. Chopra, M.; Dharmarajan, A.M.; Meiss, G.; Schrenk, D. Inhibition of UV-C light-induced apoptosis in liver cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Sci. 2009, 111, 49–63.
  59. Yuan, J.; Liu, Z.; Liu, J.; Fan, R. Circ_0060055 Promotes the Growth, Invasion, and Radioresistance of Glioblastoma by Targeting MiR-197-3p/API5 Axis. Neurotox. Res. 2022, 40, 1292–1303.
  60. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70.
  61. Burnett, J.C.; Rossi, J.J. RNA-based therapeutics: Current progress and future prospects. Chem. Biol. 2012, 19, 60–71.
  62. Feng, R.; Patil, S.; Zhao, X.; Miao, Z.; Qian, A. RNA Therapeutics—Research and Clinical Advancements. Front. Mol. Biosci. 2021, 8, 710738.
  63. Sharma, V.K.; Lahiri, M. Interplay between p300 and HDAC1 regulate acetylation and stability of Api5 to regulate cell proliferation. Sci. Rep. 2021, 11, 16427.
  64. Han, B.G.; Kim, K.H.; Lee, S.J.; Jeong, K.C.; Cho, J.W.; Noh, K.H.; Kim, T.W.; Kim, S.J.; Yoon, H.J.; Suh, S.W.; et al. Helical repeat structure of apoptosis inhibitor 5 reveals protein-protein interaction modules. J. Biol. Chem. 2012, 287, 10727–10737.
  65. Attar, N.; Kurdistani, S.K. Exploitation of EP300 and CREBBP Lysine Acetyltransferases by Cancer. Cold Spring Harb. Perspect. Med. 2017, 7, a026534.
  66. Filippakopoulos, P.; Knapp, S. Targeting bromodomains: Epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 2014, 13, 337–356.
  67. Van den Berghe, L.; Laurell, H.; Huez, I.; Zanibellato, C.; Prats, H.; Bugler, B. FIF , a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2. Mol. Endocrinol. 2000, 14, 1709–1724.
  68. Habault, J.; Thonnart, N.; Pasquereau-Kotula, E.; Bagot, M.; Bensussan, A.; Villoutreix, B.O.; Marie-Cardine, A.; Poyet, J.L. PAK1-dependent anti-tumor effect of AAC-11-derived peptides on Sézary syndrome malignant CD4+ T lymphocytes. J. Investig. Dermatol. 2021, 141, 2261–2271.
  69. Habault, J.; Thonnart, N.; Ram-Wolff, C.; Bagot, M.; Bensussan, A.; Poyet, J.-L.; Marie-Cardine, A. Validation of AAC-11-Derived Peptide Anti-Tumor Activity in a Single Graft Sezary Patient-Derived Xenograft Mouse Model. Cells 2022, 11, 2933.
  70. Jagot-Lacoussiere, L.; Kotula, E.; Villoutreix, B.O.; Bruzzoni-Giovanelli, H.; Poyet, J.L. A Cell-Penetrating Peptide Targeting AAC-11 Specifically Induces Cancer Cells Death. Cancer Res. 2016, 76, 5479–5490.
  71. Habault, J.; Kaci, A.; Pasquereau-Kotula, E.; Fraser, C.; Chomienne, C.; Dombret, H.; Braun, T.; Pla, M.; Poyet, J.-L. Prophylactic and therapeutic antileukemic effects induced by the AAC-11-derived Peptide RT53. OncoImmunology 2020, 9, 1728871.
  72. Habault, J.; Fraser, C.; Pasquereau-Kotula, E.; Born-Bony, M.; Marie-Cardine, A.; Poyet, J.-L. Efficient Therapeutic Delivery by a Novel Cell-Penetrating Peptide Derived from Acinus. Cancers 2020, 12, 1858.
  73. Pasquereau-Kotula, E.; Habault, J.; Kroemer, G.; Poyet, J.-L. The anticancer peptide RT53 induces immunogenic cell death. PLoS ONE 2018, 13, e0201220.
  74. Papo, N.; Shai, Y. Host defense peptides as new weapons in cancer treatment. Cell. Mol. Life Sci. 2005, 62, 784–790.
  75. Bong, S.M.; Bae, S.-H.; Song, B.; Gwak, H.; Yang, S.-W.; Kim, S.; Nam, S.; Rajalingam, K.; Oh, S.J.; Kim, T.W.; et al. Regulation of mRNA export through API5 and nuclear FGF2 interaction. Nucleic Acids Res. 2020, 48, 6340–6352.
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