XIAP impairs mitochondrial function during apoptosis by regulating the Bcl-2 family in renal cell carcinoma

Chen,Chao; Liu,Tian  Shu; Zhao,Si  Cong; Yang,Wen  Zheng; Chen,Zong  Ping; Yan,Yong

doi:10.3892/etm.2018.5974

XIAP impairs mitochondrial function during apoptosis by regulating the Bcl-2 family in renal cell carcinoma

Authors:
- Chao Chen
- Tian Shu Liu
- Si Cong Zhao
- Wen Zheng Yang
- Zong Ping Chen
- Yong Yan
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Affiliations: Department of Urology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China, Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, P.R. China, Department of Urology, The Affiliated Hospital of Zunyi Medical College, Zunyi 563000, P.R. China
Published online on: March 20, 2018 https://doi.org/10.3892/etm.2018.5974
Pages: 4587-4593

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Abstract

Efficient apoptosis requires Bcl-2 family-mediated mitochondrial outer membrane permeabilization (MOMP), which releases pro‑apoptotic proteins to the cytosol, activating apoptosis and inhibiting X‑linked inhibitor of apoptosis protein (XIAP). XIAP is a member of the inhibitors of apoptosis protein family whose expression is elevated in many cancer types and participates in the release of pro‑apoptotic proteins. To explore the association between XIAP and the Bcl‑2 family, and the influence of XIAP on mitochondria, RNA interference of XIAP was performed in Caki‑1 cells and the dynamic change in the levels of related proteins was compared with the original Caki‑1 cells upon induction of apoptosis. Upon knockdown of XIAP, the release of cytochrome c (Cyt‑c), second mitochondria‑derived activator of caspase (Smac) and apoptotic protease activating factor 1 (Apaf‑1) from mitochondria proceeded normally, whereas in Caki‑1 cells, the release of these pro‑apoptotic proteins was significantly prolonged, and incomplete. Downregulation of XIAP through small interfering RNA resulted in an increase of apoptosis and a marked decrease in Bcl‑2 and Bcl‑xl levels at 3 h. Additionally, the regulation of the level of XIAP protein affected the specific ratios of Bcl‑2/Bax and Bcl‑xl/Bax, which play decisive roles in cell death. In the present study, it was revealed that XIAP can feed back to mitochondria, delaying Cyt‑c and Apaf‑1 release. Furthermore, XIAP can limit the release of its inhibitor Smac with the involvement of Bcl-2 family proteins.

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1	Burz C, Berindan-Neagoe I, Balacescu O and Irimie A: Apoptosis in cancer: Key molecular signaling pathways and therapy targets. Acta Oncologica. 48:811–821. 2009. View Article : Google Scholar : PubMed/NCBI
2	Jeong SY and Seol DW: The role of mitochondria in apoptosis. BMB Rep. 41:11–22. 2008. View Article : Google Scholar : PubMed/NCBI
3	Newmeyer DD and Fergusonmiller S: Mitochondria: Releasing power for life and unleashing the machineries of death. Cell. 112:481–490. 2003. View Article : Google Scholar : PubMed/NCBI
4	Vo TT: Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 151:344–355. 2012. View Article : Google Scholar : PubMed/NCBI
5	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI
6	Chipuk JE and Green DR: How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 18:157–164. 2008. View Article : Google Scholar : PubMed/NCBI
7	Youle RJ and Strasser A: The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
8	Kvansakul M, Yang H, Fairlie WD, Czabotar PE, Fischer SF, Perugini MA, Huang DC and Colman PM: Vaccinia virus anti-apoptotic F1L is a novel Bcl-2-like domain-swapped dimer that binds a highly selective subset of BH3-containing death ligands. Cell Death Differ. 15:1564–1571. 2008. View Article : Google Scholar : PubMed/NCBI
9	Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, Macgregor GR, Thompson CB and Korsmeyer SJ: Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science. 292:727–730. 2001. View Article : Google Scholar : PubMed/NCBI
10	Li H, Zhu H, Xu CJ and Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 94:491–501. 1998. View Article : Google Scholar : PubMed/NCBI
11	Hamacher-Brady A and Brady NR: Bax/Bak-dependent, Drp1-independent Targeting of X-linked inhibitor of apoptosis protein XIAP) into inner mitochondrial compartments counteracts smac/DIABLO-dependent effector caspase activation. J Biol Chem. 290:220052015. View Article : Google Scholar : PubMed/NCBI
12	Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R and Shi Y: Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell. 11:519–527. 2003. View Article : Google Scholar : PubMed/NCBI
13	Edison N, Curtz Y, Paland N, Mamriev D, Chorubczyk N, Haviv-Reingewertz T, Kfir N, Morgenstern D, Kupervaser M, Kagan J, et al: Degradation of Bcl-2 by XIAP and ARTS promotes apoptosis. Cell Rep. 21:442–454. 2017. View Article : Google Scholar : PubMed/NCBI
14	Yan Y, Mahotka C, Heikaus S, Shibata T, Wethkamp N, Liebmann J, Suschek CV, Guo Y, Gabbert HE, Gerharz CD and Ramp U: Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas. Br J Cancer. 91:1349–1357. 2004. View Article : Google Scholar : PubMed/NCBI
15	Bilim V, Yuuki K, Itoi T, Muto A, Kato T, Nagaoka A, Motoyama T and Tomita Y: Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. Br J Cancer. 98:941–949. 2008. View Article : Google Scholar : PubMed/NCBI
16	Gavathiotis E, Reyna DE, Davis ML, Bird GH and Walensky LD: BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell. 40:481–492. 2010. View Article : Google Scholar : PubMed/NCBI
17	Tait SW and Green DR: Mitochondria and cell death: Outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 11:621–632. 2010. View Article : Google Scholar : PubMed/NCBI
18	Hamacherbrady A, Choe SC, Krijnselocker J and Brady NR: Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. Cell Death Differ. 21:1862–1876. 2014. View Article : Google Scholar : PubMed/NCBI
19	Jost PJ, Grabow S, Gray D, Mckenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, et al: XIAP discriminates between type I and type II FAS-induced apoptosis. Nature. 460:1035–1039. 2009. View Article : Google Scholar : PubMed/NCBI
20	Adams JM and Cory S: The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene. 26:1324–1337. 2007. View Article : Google Scholar : PubMed/NCBI
21	Bossy-Wetzel E, Newmeyer DD and Green DR: Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD-specific caspase activation and independently of mitochondrial transmembrane depolarization. EMBO J. 17:37–49. 1998. View Article : Google Scholar : PubMed/NCBI
22	Thomas A, El Rouby S, Reed JC, Krajewski S, Silber R, Potmesil M and Newcomb EW: Drug-induced apoptosis in B-cell chronic lymphocytic leukemia: Relationship between p53 gene mutation and bcl-2/bax proteins in drug resistance. Oncogene. 12:1055–1062. 1996.PubMed/NCBI
23	Pepper C, Hoy T and Bentley DP: Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance. Br J Cancer. 76:935–938. 1997. View Article : Google Scholar : PubMed/NCBI