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image of SMAC/DIABLO: A Guardian Angel in Boosting Anticancer Drug-Induced Apoptosis

Abstract

Apoptosis is an established hallmark of cancer. In normal conditions, apoptosis is strictly controlled; however, when it is not properly managed, it causes several complications, including cancer progression and drug resistance. SMAC/ Diablo (SMAC) is a mitochondrial protein that is released into the cytosol upon activation of BAX/BAK channels with apoptotic signals. SMAC protein interacts and neutralizes inhibitors of apoptosis (IAP) proteins and initiates the caspase cascade, which leads to apoptosis. SMAC is downregulated in several types of cancer, which led to the design of small-molecule inhibitors known as SMAC mimetics as new cancer therapeutics, and some of these molecules are in the clinical phase. It has also been shown that a combination of SMAC with standard anti-cancer drugs could be beneficial to drug-resistant cancer. Despite being a pro-apoptotic protein, it has been found that SMAC/Diablo is overexpressed in several types of cancers like lung, breast, bladder, cervix, pancreas, prostate, and colon, as well as in melanoma and glioma, and in cancer cells. Recently, we have reported that the overexpression of SMAC in cancers is essential for cell and tumor growth due to non-apoptotic regulation of phospholipid synthesis. The current review is focused on apoptotic and non-apoptotic functions of SMAC and its role in drug resistance.

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2025-05-19
2025-09-12

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References

  1. Wong R.S.Y. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res. 2011 30 1 87 10.1186/1756‑9966‑30‑87 21943236
    [Google Scholar]
  2. Palma F.R. Gantner B.N. Sakiyama M.J. ROS production by mitochondria: Function or dysfunction? Oncogene 2024 43 5 295 303 10.1038/s41388‑023‑02907‑z 38081963
    [Google Scholar]
  3. Austin S. Nowikovsky K. Mitochondrial osmoregulation in evolution, cation transport and metabolism. Biochim. Biophys. Acta Bioenerg. 2021 1862 5 148368 10.1016/j.bbabio.2021.148368 33422486
    [Google Scholar]
  4. Pandey S. Anang V. Schumacher M.M. Mitochondria driven innate immune signaling and inflammation in cancer growth, immune evasion, and therapeutic resistance. Int. Rev. Cell Mol. Biol. 2024 386 223 247 10.1016/bs.ircmb.2024.01.006 38782500
    [Google Scholar]
  5. Walker B.R. Moraes C.T. Nuclear-mitochondrial interactions. Biomolecules 2022 12 3 427 10.3390/biom12030427 35327619
    [Google Scholar]
  6. Capela e Silva F. Rodrigues C.M.P. Apoptosis-50 years after its discovery. Biomedicines 2023 11 4 1196 10.3390/biomedicines11041196 37189814
    [Google Scholar]
  7. Pandey S.K. Paul A. Shteinfer-Kuzmine A. Zalk R. Bunz U. Shoshan-Barmatz V. SMAC/Diablo controls proliferation of cancer cells by regulating phosphatidylethanolamine synthesis. Mol. Oncol. 2021 15 11 3037 3061 10.1002/1878‑0261.12959 33794068
    [Google Scholar]
  8. Pandey S.K. Shteinfer-Kuzmine A. Chalifa-Caspi V. Shoshan-Barmatz V. Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression. Front. Oncol. 2022 12 992260 10.3389/fonc.2022.992260 36185255
    [Google Scholar]
  9. Mustafa M. Ahmad R. Tantry I.Q. Apoptosis: A comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells 2024 13 22 1838 10.3390/cells13221838 39594587
    [Google Scholar]
  10. Green D.R. The death receptor pathway of apoptosis. Cold Spring Harb. Perspect. Biol. 2022 14 2 a041053 10.1101/cshperspect.a041053 35105716
    [Google Scholar]
  11. Mandal R. Barron J.C. Kostova I. Becker S. Strebhardt K. Caspase-8: The double-edged sword. Biochim. Biophys. Acta Rev. Cancer 2020 1873 2 188357 10.1016/j.bbcan.2020.188357 32147543
    [Google Scholar]
  12. Shakeri R. Kheirollahi A. Davoodi J. Contribution of Apaf-1 to the pathogenesis of cancer and neurodegenerative diseases. Biochimie 2021 190 91 110 10.1016/j.biochi.2021.07.004 34298080
    [Google Scholar]
  13. Shoshan-Barmatz V. Arif T. Shteinfer-Kuzmine A. Apoptotic proteins with non-apoptotic activity: Expression and function in cancer. Apoptosis 2023 28 5-6 730 753 10.1007/s10495‑023‑01835‑3 37014578
    [Google Scholar]
  14. Abbas R. Larisch S. Targeting xiap for promoting cancer cell death-the story of arts and smac. Cells 2020 9 3 663 10.3390/cells9030663 32182843
    [Google Scholar]
  15. Zhao X.Y. Wang X.Y. Wei Q.Y. Xu Y.M. Lau A.T.Y. Potency and selectivity of smac/diablo mimetics in solid tumor therapy. Cells 2020 9 4 1012 10.3390/cells9041012 32325691
    [Google Scholar]
  16. Santhanam M. Kumar Pandey S. Shteinfer-Kuzmine A. Interaction of SMAC with a survivin-derived peptide alters essential cancer hallmarks: Tumor growth, inflammation, and immunosuppression. Mol. Ther. 2024 32 6 1934 1955 10.1016/j.ymthe.2024.04.007 38582961
    [Google Scholar]
  17. Rafatmanesh A. Behjati M. Mobasseri N. Sarvizadeh M. Mazoochi T. Karimian M. The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer. J. Cell. Physiol. 2020 235 2 725 744 10.1002/jcp.29027 31250439
    [Google Scholar]
  18. Warrier N.M. Agarwal P. Kumar P. Emerging importance of survivin in stem cells and cancer: The development of new cancer therapeutics. Stem Cell Rev. Rep. 2020 16 5 828 852 10.1007/s12015‑020‑09995‑4 32691369
    [Google Scholar]
  19. Miles M.A. Caruso S. Baxter A.A. Poon I.K.H. Hawkins C.J. Smac mimetics can provoke lytic cell death that is neither apoptotic nor necroptotic. Apoptosis 2020 25 7-8 500 518 10.1007/s10495‑020‑01610‑8 32440848
    [Google Scholar]
  20. Harris M.A. Shekhar T.M. Miles M.A. Cerra C. Hawkins C.J. The smac mimetic LCL161 targets established pulmonary osteosarcoma metastases in mice. Clin. Exp. Metastasis 2021 38 5 441 449 10.1007/s10585‑021‑10116‑9 34398333
    [Google Scholar]
  21. Santagostino S.F. Assenmacher C.A. Tarrant J.C. Adedeji A.O. Radaelli E. Mechanisms of regulated cell death: Current perspectives. Vet. Pathol. 2021 58 4 596 623 10.1177/03009858211005537 34039100
    [Google Scholar]
  22. Archer S.L. Mitochondrial dynamics--mitochondrial fission and fusion in human diseases. N. Engl. J. Med. 2013 369 23 2236 2251 10.1056/NEJMra1215233 24304053
    [Google Scholar]
  23. Anderson G.R. Wardell S.E. Cakir M. Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat. Commun. 2018 9 1 1677 10.1038/s41467‑018‑04033‑x 29700304
    [Google Scholar]
  24. Deng Y. Lin Y. Wu X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev. 2002 16 1 33 45 10.1101/gad.949602 11782443
    [Google Scholar]
  25. Horvath S.E. Daum G. Lipids of mitochondria. Prog. Lipid Res. 2013 52 4 590 614 10.1016/j.plipres.2013.07.002 24007978
    [Google Scholar]
  26. Mejia E.M. Hatch G.M. Mitochondrial phospholipids: Role in mitochondrial function. J. Bioenerg. Biomembr. 2016 48 2 99 112 10.1007/s10863‑015‑9601‑4 25627476
    [Google Scholar]
  27. Zhang Q. Tamura Y. Roy M. Adachi Y. Iijima M. Sesaki H. Biosynthesis and roles of phospholipids in mitochondrial fusion, division and mitophagy. Cell. Mol. Life Sci. 2014 71 19 3767 3778 10.1007/s00018‑014‑1648‑6 24866973
    [Google Scholar]
  28. Liu L. Zhou L. Wang L.L. Programmed cell death in asthma: Apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. J. Inflamm. Res. 2023 16 2727 2754 10.2147/JIR.S417801 37415620
    [Google Scholar]
  29. Morrish E. Brumatti G. Silke J. Future therapeutic directions for smac-mimetics. Cells 2020 9 2 406 10.3390/cells9020406 32053868
    [Google Scholar]
  30. Pandey R. Bisht P. Wal P. Murti K. Ravichandiran V. Kumar N. Smac mimetics for the treatment of lung carcinoma: Present development and future prospects. Mini Rev. Med. Chem. 2024 24 14 1334 1352 10.2174/0113895575269644231120104501 38275029
    [Google Scholar]
  31. Jahangiri B. Saei A.K. Obi P.O. Exosomes, autophagy and er stress pathways in human diseases: Cross-regulation and therapeutic approaches. Biochim. Biophys. Acta Mol. Basis Dis. 2022 1868 10 166484 10.1016/j.bbadis.2022.166484 35811032
    [Google Scholar]
  32. Chen T. Ashwood L.M. Kondrashova O. Strasser A. Kelly G. Sutherland K.D. Breathing new insights into the role of mutant p53 in lung cancer. Oncogene 2025 44 3 115 129 10.1038/s41388‑024‑03219‑6 39567755
    [Google Scholar]
  33. Jin H.R. Wang J. Wang Z.J. Lipid metabolic reprogram-ming in tumor microenvironment: From mechanisms to therapeutics. J. Hematol. Oncol. 2023 16 1 103 10.1186/s13045‑023‑01498‑2 37700339
    [Google Scholar]
  34. Cockcroft S. Mammalian lipids: Structure, synthesis and function. Essays Biochem. 2021 65 5 813 845 10.1042/EBC20200067 34415021
    [Google Scholar]
  35. Simoes I.C.M. Morciano G. Lebiedzinska-Arciszewska M. The mystery of mitochondria-er contact sites in physiology and pathology: A cancer perspective. Biochim. Biophys. Acta Mol. Basis Dis. 2020 1866 10 165834 10.1016/j.bbadis.2020.165834 32437958
    [Google Scholar]
  36. Mishima E. Ito J. Wu Z. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 2022 608 7924 778 783 10.1038/s41586‑022‑05022‑3 35922516
    [Google Scholar]
  37. Ren Y. Wang M. Yuan H. Wang Z. Yu L. A novel insight into cancer therapy: Lipid metabolism in tumor-associated macrophages. Int. Immunopharmacol. 2024 135 112319 10.1016/j.intimp.2024.112319 38801810
    [Google Scholar]
  38. Zhao H. Wang T. PE homeostasis rebalanced through mitochondria-ER lipid exchange prevents retinal degeneration in Drosophila. PLoS Genet. 2020 16 10 e1009070 10.1371/journal.pgen.1009070 33064773
    [Google Scholar]
  39. Chakraborty S. Nandi P. Mishra J. Molecular mechanisms in regulation of autophagy and apoptosis in view of epigenetic regulation of genes and involvement of liquid-liquid phase separation. Cancer Lett. 2024 587 216779 10.1016/j.canlet.2024.216779 38458592
    [Google Scholar]
  40. Kopecka J. Trouillas P. Gašparović A.Č. Gazzano E. Assaraf Y.G. Riganti C. Phospholipids and cholesterol: Inducers of cancer multidrug resistance and therapeutic targets. Drug Resist. Updat. 2020 49 100670 10.1016/j.drup.2019.100670 31846838
    [Google Scholar]
  41. Abouzeid F.M.A. Alshammery S. Characterization and utilization of apple peel and grape stems extract constituents as green restraints for aluminum dissolution. Sci. Rep. 2024 14 1 24170 10.1038/s41598‑024‑73592‑5 39406747
    [Google Scholar]
  42. Kaloni D. Diepstraten S.T. Strasser A. Kelly G.L. BCL-2 protein family: Attractive targets for cancer therapy. Apoptosis 2023 28 1-2 20 38 10.1007/s10495‑022‑01780‑7 36342579
    [Google Scholar]
  43. Snacel-Fazy E. Soubéran A. Grange M. SMAC mimetic drives microglia phenotype and glioblastoma immune microenvironment. Cell Death Dis. 2024 15 9 676 10.1038/s41419‑024‑07056‑z 39278921
    [Google Scholar]
  44. Xu W. Fang F. Wang Y. Co-overexpression of TRAIL and Smac sensitizes MDA-MB-231 cells to radiation through apoptosis depending on mitochondrial pathway. Radiat. Environ. Biophys. 2022 61 1 37 48 10.1007/s00411‑021‑00961‑3 35006369
    [Google Scholar]
  45. Maji A. Paul A. Sarkar A. Significance of TRAIL/Apo-2 ligand and its death receptors in apoptosis and necroptosis signalling: Implications for cancer-targeted therapeutics. Biochem. Pharmacol. 2024 221 116041 10.1016/j.bcp.2024.116041 38316367
    [Google Scholar]
  46. Zhang B. Yang C. Wang R. OTUD7B suppresses Smac mimetic-induced lung cancer cell invasion and migration via deubiquitinating TRAF3. J. Exp. Clin. Cancer Res. 2020 39 1 244 10.1186/s13046‑020‑01751‑3 33198776
    [Google Scholar]
  47. Carneiro B.A. El-Deiry W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 2020 17 7 395 417 10.1038/s41571‑020‑0341‑y 32203277
    [Google Scholar]
  48. Montinaro A. Walczak H. Harnessing TRAIL-induced cell death for cancer therapy: A long walk with thrilling discoveries. Cell Death Differ. 2023 30 2 237 249 10.1038/s41418‑022‑01059‑z 36195672
    [Google Scholar]
  49. Yu X. Cao W. Yang X. Prognostic value and therapeutic potential of IAP family in head and neck squamous cell carcinoma. Aging (Albany NY) 2024 16 4 3674 3693 10.18632/aging.205551 38364254
    [Google Scholar]
  50. Güllülü Ö. Hehlgans S. Rödel C. Fokas E. Rödel F. Tumor suppressor protein p53 and inhibitor of apoptosis proteins in colorectal cancer-a promising signaling network for therapeutic interventions. Cancers (Basel) 2021 13 4 624 10.3390/cancers13040624 33557398
    [Google Scholar]
  51. Deka K. Li Y. Transcriptional regulation during aberrant activation of nf-kappab signalling in cancer. Cells 2023 12 5 788 10.3390/cells12050788 36899924
    [Google Scholar]
  52. Dumétier B. Zadoroznyj A. Dubrez L. Iap-mediated protein ubiquitination in regulating cell signaling. Cells 2020 9 5 1118 10.3390/cells9051118 32365919
    [Google Scholar]
  53. Hanifeh M. Ataei F. XIAP as a multifaceted molecule in cellular signaling. Apoptosis 2022 27 7-8 441 453 10.1007/s10495‑022‑01734‑z 35661061
    [Google Scholar]
  54. He L. Sehrawat T.S. Verma V.K. Xiap knockdown in alcohol-associated liver disease models exhibits divergent in vitro and in vivo phenotypes owing to a potential zonal inhibitory role of smac. Front. Physiol. 2021 12 664222 10.3389/fphys.2021.664222 34025452
    [Google Scholar]
  55. Krzykawski K. Kubina R. Wendlocha D. Sarna R. Mielczarek-Palacz A. Multifaceted evaluation of inhibitors of anti-apoptotic proteins in head and neck cancer: Insights from in vitro, in vivo, and clinical studies. Pharmaceuticals 2024 17 10 1308 10.3390/ph17101308 39458950
    [Google Scholar]
  56. Shibuya Y. Kudo K. Zeligs K.P. Smac mimetics synergistically cooperate with hdac inhibitors enhancing tnf-alpha autocrine signaling. Cancers (Basel) 2023 15 4 1315 10.3390/cancers15041315 36831656
    [Google Scholar]
  57. Bose D. Roy L. Chatterjee S. Peptide therapeutics in the management of metastatic cancers. RSC Advances 2022 12 33 21353 21373 10.1039/D2RA02062A 35975072
    [Google Scholar]
  58. Salimi-Jeda A Ghabeshi S Autophagy modulation and cancer combination therapy: A smart approach in cancer therapy. Cancer Treat. Res. Commun. 2022 30 100512 10.1016/j.ctarc.2022.100512 35026533
    [Google Scholar]
  59. Kondapuram S.K. Ramachandran H.K. Arya H. Coumar M.S. Targeting survivin for cancer therapy: Strategies, small molecule inhibitors and vaccine based therapeutics in development. Life Sci. 2023 335 122260 10.1016/j.lfs.2023.122260 37963509
    [Google Scholar]
  60. Chan K.I. Zhang S. Li G. Myc oncogene: A druggable target for treating cancers with natural products. Aging Dis. 2024 15 2 640 697 10.14336/AD.2023.0520 37450923
    [Google Scholar]
  61. Meier P. Legrand A.J. Adam D. Silke J. Immunogenic cell death in cancer: Targeting necroptosis to induce antitumour immunity. Nat. Rev. Cancer 2024 24 5 299 315 10.1038/s41568‑024‑00674‑x 38454135
    [Google Scholar]
  62. Raja A. Kasana A. Verma V. Next-generation therapeutic antibodies for cancer treatment: Advancements, applications, and challenges. Mol. Biotechnol. 2024 10.1007/s12033‑024‑01270‑y 39222285
    [Google Scholar]
  63. Bukowski K. Kciuk M. Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci. 2020 21 9 3233 10.3390/ijms21093233 32370233
    [Google Scholar]
  64. Boccellato C. Rehm M. Trail-induced apoptosis and proteasomal activity - mechanisms, signalling and interplay. Biochim. Biophys. Acta Mol. Cell Res. 2024 1871 4 119688 10.1016/j.bbamcr.2024.119688 38368955
    [Google Scholar]
  65. Luo C. He S. Shi F. Zhou J. Shang L. The role of trail signaling in cancer: Searching for new therapeutic strategies. Biology (Basel) 2024 13 7 521 10.3390/biology13070521 39056714
    [Google Scholar]
  66. Chang Y.C. Kondapuram S.K. Yang T.H. The SMAC mimetic LCL161 is a direct ABCB1/MDR1-ATPase activity modulator and BIRC5/Survivin expression down-regulator in cancer cells. Toxicol. Appl. Pharmacol. 2020 401 115080 10.1016/j.taap.2020.115080 32497533
    [Google Scholar]
  67. Rambow A.C. Aschenbach I. Hagelund S. Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells. Front. Cell Dev. Biol. 2022 10 942718 10.3389/fcell.2022.942718 36158196
    [Google Scholar]
  68. Thapa B. Kc R. Uludağ H. TRAIL therapy and prospective developments for cancer treatment. J. Control. Release 2020 326 335 349 10.1016/j.jconrel.2020.07.013 32682900
    [Google Scholar]
  69. Zhang Y. Zhou X. Targeting regulated cell death (RCD) in hematological malignancies: Recent advances and therapeutic potential. Biomed. Pharmacother. 2024 175 116667 10.1016/j.biopha.2024.116667 38703504
    [Google Scholar]
  70. Cheung C.H.A. Chang Y.C. Lin T.Y. Cheng S.M. Leung E. Anti-apoptotic proteins in the autophagic world: An update on functions of XIAP, Survivin, and BRUCE. J. Biomed. Sci. 2020 27 1 31 10.1186/s12929‑020‑0627‑5 32019552
    [Google Scholar]
  71. Shahar N. Larisch S. Inhibiting the inhibitors: Targeting anti-apoptotic proteins in cancer and therapy resistance. Drug Resist. Updat. 2020 52 100712 10.1016/j.drup.2020.100712 32599435
    [Google Scholar]
  72. Abbas R. Larisch S. Killing by degradation: Regulation of apoptosis by the ubiquitin-proteasome-system. Cells 2021 10 12 3465 10.3390/cells10123465 34943974
    [Google Scholar]
  73. Ni G. Chen S. Chen M. Host-defense peptides caerin 1.1 and 1.9 stimulate tnf-alpha-dependent apoptotic signals in human cervical cancer hela cells. Front. Cell Dev. Biol. 2020 8 676 10.3389/fcell.2020.00676 32850805
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240380871250518032318
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SMAC/DIABLO: A Guardian Angel in Boosting Anticancer Drug-Induced Apoptosis
Bentham Science Publishers ; https://doi.org/10.2174/0115665240380871250518032318
/content/journals/cmm/10.2174/0115665240380871250518032318
/content/journals/cmm/10.2174/0115665240380871250518032318
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  • Article Type:     Review Article
Keywords: Cancer ; drug target ; SMAC/diablo ; drug resistance ; apoptosis

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