Key necroptotic proteins are required for Smac mimetic-mediated sensitization of cholangiocarcinoma cells to TNF-α and chemotherapeutic gemcitabine-induced necroptosis

English version

Autoři: Perawatt Akara-amornthum ^aff001; Thanpisit Lomphithak ^aff001; Swati Choksi ^aff002; Rutaiwan Tohtong ^aff003; Siriporn Jitkaew ^aff004
Působiště autorů: Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand ^aff001; Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Convent Drive, Bethesda, MD, United States of America ^aff002; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand ^aff003; Age-Related Inflammation and Degeneration Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand ^aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227454

Souhrn

Cholangiocarcinoma (CCA), a malignant tumor originating in the biliary tract, is well known to be associated with adverse clinical outcomes and high mortality rates due to the lack of effective therapy. Evasion of apoptosis is considered a key contributor to therapeutic success and chemotherapy resistance in CCA, highlighting the need for novel therapeutic strategies. In this study, we demonstrated that the induction of necroptosis, a novel regulated form of necrosis, could potentially serve as a novel therapeutic approach for CCA patients. The RNA sequencing data in The Cancer Genome Atlas (TCGA) database were analyzed and revealed that both receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), two essential mediators of necroptosis, were upregulated in CCA tissues when compared with the levels in normal bile ducts. We demonstrated in a panel of CCA cell lines that RIPK3 was differentially expressed in CCA cell lines, while MLKL was more highly expressed in CCA cell lines than in nontumor cholangiocytes. We therefore showed that treatment with both tumor necrosis factor-α (TNF-α) and Smac mimetic, an inhibitor of apoptosis protein (IAP) antagonist, induced RIPK1/RIPK3/MLKL-dependent necroptosis in CCA cells when caspases were blocked. The necroptotic induction in a panel of CCA cells was correlated with RIPK3 expression. Intriguingly, we demonstrated that Smac mimetic sensitized CCA cells to a low dose of standard chemotherapy, gemcitabine, and induced necroptosis in an RIPK1/RIPK3/MLKL-dependent manner upon caspase inhibition but not in nontumor cholangiocytes. We further demonstrated that Smac mimetic and gemcitabine synergistically induced an increase in TNF-α mRNA levels and that Smac mimetic reversed gemcitabine-induced cell cycle arrest, leading to cell killing. Collectively, our present study demonstrated that TNF-α and gemcitabine induced RIPK1/RIPK3/MLKL-dependent necroptosis upon IAP depletion and caspase inhibition; therefore, our findings have pivotal implications for designing a novel necroptosis-based therapeutic strategy for CCA patients.

Klíčová slova:

Apoptosis – Cell cycle and cell division – Cell cycle inhibitors – Cell death – Cell staining – Cytokines – Flow cytometry – Necrotic cell death

Zdroje

1. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma-evolving concepts and therapeutic strategies. Nature Reviews Clinical Oncology. 2018;15(2):95–111. doi: 10.1038/nrclinonc.2017.157 28994423

2. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nature Reviews Gastroenterology and Hepatology. 2016;13(5):261–80. doi: 10.1038/nrgastro.2016.51 27095655

3. Eckmann KR, Patel DK, Landgraf A, Slade JH, Lin E, Kaur H, et al. Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: A retrospective analysis. Gastrointestinal Cancer Research. 2011;4(5–6):155–60. 22295126

4. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New England Journal of Medicine. 2010;362(14):1273–81. doi: 10.1056/NEJMoa0908721 20375404

5. Okusaka T, Nakachi K, Fukutomi A, Mizuno N, Ohkawa S, Funakoshi A, et al. Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: A comparative multicentre study in Japan. British Journal of Cancer. 2010;103(4):469–74. doi: 10.1038/sj.bjc.6605779 20628385

6. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013 21376230

7. Marin JJG, Lozano E, Briz O, Al-Abdulla R, Serrano MA, Macias RIR. Molecular bases of chemoresistance in cholangiocarcinoma. Current Drug Targets. 2017;18(8):889–900. doi: 10.2174/1389450116666150223121508 25706108

8. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nature Reviews Molecular Cell Biology. 2010;11(10):700–14. doi: 10.1038/nrm2970 20823910

9. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114(2):181–90. doi: 10.1016/s0092-8674(03)00521-x 12887920

10. Wang L, Du F, Wang X. TNF-α induces two distinct caspase-8 activation pathways. Cell. 2008;133(4):693–703. doi: 10.1016/j.cell.2008.03.036 18485876

11. Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunology. 2000;1(6):489–95. doi: 10.1038/82732 11101870

12. Cho Y, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation. Cell. 2009;137(6):1112–23. doi: 10.1016/j.cell.2009.05.037 19524513

13. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α. Cell. 2009;137(6):1100–11. doi: 10.1016/j.cell.2009.05.021 19524512

14. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325(5938):332–6. doi: 10.1126/science.1172308 19498109

15. Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nature Cell Biology. 2014;16(1):55–65. doi: 10.1038/ncb2883 24316671

16. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148(1–2):213–27. doi: 10.1016/j.cell.2011.11.031 22265413

17. Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(14):5322–7. doi: 10.1073/pnas.1200012109 22421439

18. Krysko O, Aaes TL, Kagan VE, D'Herde K, Bachert C, Leybaert L, et al. Necroptotic cell death in anti-cancer therapy. Immunological Reviews. 2017;280(1):207–19. doi: 10.1111/imr.12583 29027225

19. Yatim N, Cullen S, Albert ML. Dying cells actively regulate adaptive immune responses. Nature Reviews Immunology. 2017;17(4):262–75. doi: 10.1038/nri.2017.9 28287107

20. Snyder AG, Hubbard NW, Messmer MN, Kofman SB, Hagan CE, Orozco SL, et al. Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Science Immunology. 2019;4(36):eaaw2004.

21. Su Z, Yang Z, Xie L, Dewitt JP, Chen Y. Cancer therapy in the necroptosis era. Cell Death and Differentiation. 2016;23(5):748–56. doi: 10.1038/cdd.2016.8 26915291

22. Nugues AL, El Bouazzati H, Hétuin D, Berthon C, Loyens A, Bertrand E, et al. RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell Death and Disease. 2014;5(8). doi: 10.1038/cddis.2014.347 25144719

23. Feng X, Song Q, Yu A, Tang H, Peng Z, Wang X. Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma. 2015;62(4):592–601. doi: 10.4149/neo_2015_071 25997957

24. Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Research. 2015;25(6):707–25. doi: 10.1038/cr.2015.56 25952668

25. Moriwaki K, Bertin J, Gough PJ, Orlowski GM, Chan FKM. Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death and Disease. 2015;6(2). doi: 10.1038/cddis.2015.16 25675296

26. Ruan J, Mei L, Zhu Q, Shi G, Wang H. Mixed lineage kinase domain-like protein is a prognostic biomarker for cervical squamous cell cancer. International Journal of Clinical and Experimental Pathology. 2015;8(11):15035–8. 26823841

27. Stoll G, Ma Y, Yang H, Kepp O, Zitvogel L, Kroemer G. Pro-necrotic molecules impact local immunosurveillance in human breast cancer. OncoImmunology. 2017;6(4). doi: 10.1080/2162402X.2017.1299302 28507808

28. Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka B, Shelton JW, et al. Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma. Cancer. 2013;119(17):3148–55. doi: 10.1002/cncr.28144 23720157

29. Geserick P, Wang J, Schilling R, Horn S, Harris PA, Bertin J, et al. Absence of RIPK3 predicts necroptosis resistance in malignant melanoma. Cell Death and Disease. 2015;6(9). doi: 10.1038/cddis.2015.240 26355347

30. Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nature Reviews Drug Discovery. 2012;11(2):109–24. doi: 10.1038/nrd3627 22293567

31. Fulda S. Molecular pathways: Targeting inhibitor of apoptosis proteins in cancer-from molecular mechanism to therapeutic application. Clinical Cancer Research. 2014;20(2):289–95. doi: 10.1158/1078-0432.CCR-13-0227 24270683

32. Gyrd-Hansen M, Meier P. IAPs: From caspase inhibitors to modulators of NF-κB, inflammation and cancer. Nature Reviews Cancer. 2010;10(8):561–74. doi: 10.1038/nrc2889 20651737

33. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, et al. IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis. Cell. 2007;131(4):669–81. doi: 10.1016/j.cell.2007.10.030 18022362

34. Vince JE, Wong WW-L, Khan N, Feltham R, Chau D, Ahmed AU, et al. IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis. Cell. 2007;131(4):682–93. https://doi.org/10.1016/j.cell.2007.10.037. 18022363

35. Mohamed MS, Bishr MK, Almutairi FM, Ali AG. Inhibitors of apoptosis: clinical implications in cancer. Apoptosis. 2017;22(12):1487–509. doi: 10.1007/s10495-017-1429-4 29067538

36. Fingas CD, Blechacz BRA, Smoot RL, Guicciardi ME, Mott J, Bronk SF, et al. A smac mimetic reduces TNF related apoptosis inducing ligand (TRAIL)-induced invasion and metastasis of cholangiocarcinoma cells. Hepatology. 2010;52(2):550–61. doi: 10.1002/hep.23729 20683954

37. Wehrkamp CJ, Gutwein AR, Natarajan SK, Phillippi MA, Mott JL. XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells. PLoS ONE. 2014;9(3). doi: 10.1371/journal.pone.0090238 24603802

38. Fulda S. Promises and challenges of Smac mimetics as cancer therapeutics. Clinical Cancer Research. 2015;21(22):5030–6. doi: 10.1158/1078-0432.CCR-15-0365 26567362

39. Sirisinha S, Tengchaisri T, Boonpucknavig S, Prempracha N, Ratanarapee S, Pausawasdi A. Establishment and characterization of a cholangiocarcinoma cell line from a Thai patient with intrahepatic bile duct cancer. Asian Pacific Journal of Allergy and Immunology. 1991;9(2):153–7. 1666951

40. Rattanasinganchan P, Leelawat K, Treepongkaruna SA, Tocharoentanaphol C, Subwongcharoen S, Suthiphongchai T, et al. Establishment and characterization of a cholangiocarcinoma cell line (RMCCA-1) from a Thai patient. World Journal of Gastroenterology. 2006;12(40):6500–6. doi: 10.3748/wjg.v12.i40.6500 17072981

41. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic acids research. 2017;45(W1):W98–W102. doi: 10.1093/nar/gkx247 28407145

42. Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nature Protocols. 2013;8(11):2281–308. doi: 10.1038/nprot.2013.143 24157548

43. Chou T-C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer research. 2010:0008–5472. CAN-09-1947.

44. Livak KJ, Schmittgen TD. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods. 2001;25(4):402–8. doi: 10.1006/meth.2001.1262 11846609

45. Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, et al. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 2011;43(3):449–63. doi: 10.1016/j.molcel.2011.06.011 21737330

46. Yang H, Ma Y, Chen G, Zhou H, Yamazaki T, Klein C, et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. Oncoimmunology. 2016;5(6):e1149673. doi: 10.1080/2162402X.2016.1149673 27471616

47. Thibault B, Genre L, Le Naour A, Broca C, Mery E, Vuagniaux G, et al. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Scientific Reports. 2018;8(1). doi: 10.1038/s41598-017-18329-3

48. Czaplinski S, Abhari BA, Torkov A, Seggewiß D, Hugle M, Fulda S. Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells. Oncotarget. 2015;6(39):41522–34. doi: 10.18632/oncotarget.6308 26575016

49. Chromik J, Safferthal C, Serve H, Fulda S. Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis. Cancer Letters. 2014;344(1):101–9. doi: 10.1016/j.canlet.2013.10.018 24184825

50. Wagner L, Marschall V, Karl S, Cristofanon S, Zobel K, Deshayes K, et al. Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1- and NF-κB-dependent manner. Oncogene. 2013;32(8):988–97. doi: 10.1038/onc.2012.108 22469979

51. Lee EK, Goodwin Jinesh G, Laing NM, Choi W, McConkey DJ, Kamat AM. A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin. Cancer Biology and Therapy. 2013;14(9):1–11. doi: 10.4161/cbt.25326 23792592

52. Löder S, Fakler M, Schoeneberger H, Cristofanon S, Leibacher J, Vanlangenakker N, et al. RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. Leukemia. 2012;26(5):1020–9. doi: 10.1038/leu.2011.353 22173242

53. Greer RM, Peyton M, Larsen JE, Girard L, Xie Y, Gazdar AF, et al. SMAC mimetic (JP1201) sensitizes non-small cell lung cancers to multiple chemotherapy agents in an IAP-dependent but TNF-α-independent manner. Cancer Research. 2011;71(24):7640–8. doi: 10.1158/0008-5472.CAN-10-3947 22049529

54. Probst BL, Liu L, Ramesh V, Li L, Sun H, Minna JD, et al. Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner. Cell Death and Differentiation. 2010;17(10):1645–54. doi: 10.1038/cdd.2010.44 20431601

55. Dineen SP, Roland CL, Greer R, Carbon JG, Toombs JE, Gupta P, et al. Smac mimetic increases chemotherapy response and improves survival in mice with pancreatic cancer. Cancer Research. 2010;70(7):2852–61. doi: 10.1158/0008-5472.CAN-09-3892 20332237

56. Steinhart L, Belz K, Fulda S. Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosis. Cell death & disease. 2013;4(9):e802.

57. Stadel D, Cristofanon S, Abhari BA, Deshayes K, Zobel K, Vucic D, et al. Requirement of nuclear factor κB for smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. Neoplasia. 2011;13(12):1162–70. doi: 10.1593/neo.11460 22241962

58. Brumatti G, Ma C, Lalaoui N, Nguyen N-Y, Navarro M, Tanzer MC, et al. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Science translational medicine. 2016;8(339):339ra69-ra69.

59. Min D-J, He S, Green JE. Birinapant (TL32711) improves responses to GEM/AZD7762 combination therapy in triple-negative breast cancer cell lines. Anticancer research. 2016;36(6):2649–57. 27272773

60. Biton S, Ashkenazi A. NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-α feedforward signaling. Cell. 2011;145(1):92–103. doi: 10.1016/j.cell.2011.02.023 21458669

61. Montano R, Khan N, Hou H, Seigne J, Ernstoff MS, Lewis LD, et al. Cell cycle perturbation induced by gemcitabine in human tumor cells in cell culture, xenografts and bladder cancer patients: implications for clinical trial designs combining gemcitabine with a Chk1 inhibitor. Oncotarget. 2017;8(40):67754. doi: 10.18632/oncotarget.18834 28978069

62. Cook WD, Moujalled DM, Ralph TJ, Lock P, Young SN, Murphy JM, et al. RIPK1-and RIPK3-induced cell death mode is determined by target availability. Cell Death and Differentiation. 2014;21(10):1600–12. doi: 10.1038/cdd.2014.70 24902899

63. Xu B, Xu M, Tian Y, Yu Q, Zhao Y, Chen X, et al. Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells. Cell death discovery. 2017;3:16096. doi: 10.1038/cddiscovery.2016.96 28179994

64. Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532(7598):245–9. doi: 10.1038/nature17403 27049944

65. Yatim N, Jusforgues-Saklani H, Orozco S, Schulz O, da Silva RB, e Sousa CR, et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science. 2015;350(6258):328–34. doi: 10.1126/science.aad0395 26405229

66. Aaes TL, Kaczmarek A, Delvaeye T, De Craene B, De Koker S, Heyndrickx L, et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell reports. 2016;15(2):274–87. doi: 10.1016/j.celrep.2016.03.037 27050509

67. Van Hoecke L, Van Lint S, Roose K, Van Parys A, Vandenabeele P, Grooten J, et al. Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes. Nature communications. 2018;9(1):3417. doi: 10.1038/s41467-018-05979-8 30143632

68. Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ, et al. Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Research. 2004;64(10):3517–24. doi: 10.1158/0008-5472.CAN-03-2770 15150106

69. Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology. 2005;128(7):2054–65. doi: 10.1053/j.gastro.2005.03.010 15940637

70. DiPersio JF, Erba HP, Larson RA, Luger SM, Tallman MS, Brill JM, et al. Oral Debio1143 (AT406), an antagonist of inhibitor of apoptosis proteins, combined with daunorubicin and cytarabine in patients with poor-risk acute myeloid leukemia—results of a phase I dose-escalation study. Clinical Lymphoma Myeloma and Leukemia. 2015;15(7):443–9.

Key necroptotic proteins are required for Smac mimetic-mediated sensitization of cholangiocarcinoma cells to TNF-α and chemotherapeutic gemcitabine-induced necroptosis

Souhrn

Klíčová slova:

Zdroje

PLOS One

Současné pohledy na riziko v parodontologii

Svět praktické medicíny 3/2024 (znalostní test z časopisu)

Kardiologické projevy hypereozinofilií

Střevní příprava před kolonoskopií

Aktuální možnosti diagnostiky a léčby litiáz