Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer

Jin,Gongsheng; Lan,Yadong; Han,Fusheng; Sun,Yiming; Liu,Zhe; Zhang,Mingliang; Liu,Xianfu; Zhang,Xiaojing; Hu,Jianguo; Liu,Hao; Wang,Benzhong

doi:10.3892/mmr.2015.4542

Smac mimetic‑induced caspase‑independent necroptosis requires RIP1 in breast cancer

Authors:
- Gongsheng Jin
- Yadong Lan
- Fusheng Han
- Yiming Sun
- Zhe Liu
- Mingliang Zhang
- Xianfu Liu
- Xiaojing Zhang
- Jianguo Hu
- Hao Liu
- Benzhong Wang
View Affiliations

Affiliations: Department of Breast Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China, Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
Published online on: November 10, 2015 https://doi.org/10.3892/mmr.2015.4542
Pages: 359-366

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial‑derived activator of caspase/direct IAP‑binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA‑MB‑231 and MCF‑7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161‑dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor‑interacting protein kinase‑1 via small interfering RNA protected the cells from LCL161‑induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
2	Bray F, Ren JS, Masuyer E and Ferlay J: Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 132:1133–1145. 2013. View Article : Google Scholar
3	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
4	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
5	Sherr CJ: Cancer cell cycles. Science. 274:1672–1677. 1996. View Article : Google Scholar : PubMed/NCBI
6	Higgins MJ and Baselga J: Targeted therapies for breast cancer. J Clin Invest. 121:3797–3803. 2011. View Article : Google Scholar : PubMed/NCBI
7	Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 98:10869–10874. 2001. View Article : Google Scholar : PubMed/NCBI
8	Bourdeanu L and Luu T: Targeted therapies in breast cancer: Implications for advanced oncology practice. J Adv Pract Oncol. 5:246–260. 2014.
9	Reed JC: Apoptosis-based therapies. Nat Rev Drug Discov. 1:111–121. 2002. View Article : Google Scholar : PubMed/NCBI
10	Johnstone RW, Ruefli AA and Lowe SW: Apoptosis: A link between cancer genetics and chemotherapy. Cell. 108:153–164. 2002. View Article : Google Scholar : PubMed/NCBI
11	Lockshin RA and Williams CM: Programmed cell Death-I. Cytology of degeneration in the intersegmental muscles of the pernyi silkmoth. J Insect Physiol. 11:123–133. 1965. View Article : Google Scholar : PubMed/NCBI
12	Fulda S and Debatin KM: Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 25:4798–4811. 2006. View Article : Google Scholar : PubMed/NCBI
13	Bai L, Smith DC and Wang S: Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther. 144:82–95. 2014. View Article : Google Scholar : PubMed/NCBI
14	Dubrez L, Berthelet J and Glorian V: IAP proteins as targets for drug development in oncology. Onco Targets Ther. 9:1285–1304. 2013. View Article : Google Scholar : PubMed/NCBI
15	Du C, Fang M, Li Y, Li L and Wang X: Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 102:33–42. 2000. View Article : Google Scholar : PubMed/NCBI
16	Salvesen GS and Duckett CS: IAP proteins: Blocking the road to death's door. Nat Rev Mol Cell Biol. 3:401–410. 2002. View Article : Google Scholar : PubMed/NCBI
17	Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, et al: The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 150:339–350. 2012. View Article : Google Scholar : PubMed/NCBI
18	Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B and Tschopp J: Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol. 1:489–495. 2000. View Article : Google Scholar
19	Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ and Han J: RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 325:332–336. 2009. View Article : Google Scholar : PubMed/NCBI
20	Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X and Wang X: Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148:213–227. 2012. View Article : Google Scholar : PubMed/NCBI
21	Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, et al: Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 4:313–321. 2008. View Article : Google Scholar : PubMed/NCBI
22	Smith CC, Davidson SM, Lim SY, Simpkin JC, Hothersall JS and Yellon DM: Necrostatin: A potentially novel cardioprotective agent? Cardiovasc Drugs Ther. 21:227–233. 2007. View Article : Google Scholar : PubMed/NCBI
23	Linkermann A, Bräsen JH, Himmerkus N, Liu S, Huber TB, Kunzendorf U and Krautwald S: Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 81:751–761. 2012. View Article : Google Scholar : PubMed/NCBI
24	Oerlemans MI, Liu J, Arslan F, den Ouden K, van Middelaar BJ, Doevendans PA and Sluijter JP: Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo. Basic Res Cardiol. 107:2702012. View Article : Google Scholar : PubMed/NCBI
25	Lin J, Li H, Yang M, Ren J, Huang Z, Han F, Huang J, Ma J, Zhang D, Zhang Z, et al: A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep. 3:200–210. 2013. View Article : Google Scholar : PubMed/NCBI
26	Chen KF, Lin JP, Shiau CW, Tai WT, Liu CY, Yu HC, Chen PJ and Cheng AL: Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem Pharmacol. 84:268–277. 2012. View Article : Google Scholar : PubMed/NCBI
27	Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, et al: IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation and TNFalpha-dependent apoptosis. Cell. 131:669–681. 2007. View Article : Google Scholar : PubMed/NCBI
28	Weisberg E, Ray A, Barrett R, Nelson E, Christie AL, Porter D, Straub C, Zawel L, Daley JF, Lazo-Kallanian S, et al: Smac mimetics: Implications for enhancement of targeted therapies in Leukemia. Leukemia. 24:2100–2109. 2010. View Article : Google Scholar : PubMed/NCBI
29	Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol. 23:4265–4274. 2005. View Article : Google Scholar : PubMed/NCBI
30	Lowe SW and Lin AW: Apoptosis in cancer. Carcinogenesis. 21:485–495. 2000. View Article : Google Scholar : PubMed/NCBI
31	Wang S, Bai L, Lu J, Liu L, Yang CY and Sun H: Targeting inhibitors of apoptosis proteins (IAP) for new breast cancer therapeutics. J Mammary Gland Biol Neoplasia. 17:217–228. 2012. View Article : Google Scholar : PubMed/NCBI
32	Hassan M, Watari H, AbuAlmaaty A, Ohba Y and Sakuragi N: Apoptosis and molecular targeting therapy in cancer. Biomed Res Int. 2014:1508452014. View Article : Google Scholar : PubMed/NCBI
33	Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X and Shi Y: Structural basis of IAP recognition by Smac/DIABLO. Nature. 408:1008–1012. 2000. View Article : Google Scholar
34	Chauhan D, Neri P, Velankar M, Podar K, Hideshima T, Fulciniti M, Tassone P, Raje N, Mitsiades C, Mitsiades N, et al: Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM). Blood. 109:1220–1227. 2007. View Article : Google Scholar
35	Adams JM and Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
36	Kvanskul M and Hinds MG: Structural biology of the Bcl-2 family and its mimicry by viral proteins. Cell Death Dis. 4:e9092013. View Article : Google Scholar
37	Kim BM and Chung HW: Desferrioxamine (DFX) induces apoptosis through the p38-caspase8-Bid-Bax pathway in PHA-stimulated human lymphocytes. Toxicol Appl Pharmacol. 228:24–31. 2008. View Article : Google Scholar : PubMed/NCBI
38	Kozopas KM, Yang T, Buchan HL, Zhou P and Craig RW: MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. Proc Natl Acad Sci USA. 90:3516–3520. 1993. View Article : Google Scholar : PubMed/NCBI
39	Sano M, Hayashi E, Murakami H, Kishimoto H, Fukuzawa R and Nemoto N: Mcl-1, an anti-apoptotic Bcl-2 family member, essentially overlaps with insulin-producing cells in neonatal nesidioblastosis. Virchows Arch. 452:469–470. 2008. View Article : Google Scholar : PubMed/NCBI
40	Gyrd-Hansen M, Darding M, Miasari M, Santoro MM, Zender L, Xue W, Tenev T, da Fonseca PC, Zvelebil M, Bujnicki JM, et al: IAPs contain an evolutionarily conserved ubiquitin-binding domain that regulates NF-kappaB as well as cell survival and oncogenesis. Nat Cell Biol. 10:1309–1317. 2008. View Article : Google Scholar : PubMed/NCBI
41	Vaux DL and Silke J: IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol. 6:287–297. 2005. View Article : Google Scholar : PubMed/NCBI
42	Park SM, Yoon JB and Lee TH: Receptor interacting protein is ubiquitinated by cellular inhibitor of apoptosis proteins (c-IAP1 and c-IAP2) in vitro. FEBS Lett. 566:151–156. 2004. View Article : Google Scholar : PubMed/NCBI