HAX-1 inhibits apoptosis in prostate cancer through the suppression of caspase-9 activation

Yan,Jiliang; Ma,Chunyan; Cheng,Jian; Li,Zhengguo; Liu,Chao

doi:10.3892/or.2015.4202

HAX-1 inhibits apoptosis in prostate cancer through the suppression of caspase-9 activation

Authors:
- Jiliang Yan
- Chunyan Ma
- Jian Cheng
- Zhengguo Li
- Chao Liu
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Affiliations: Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng, Henan 475000, P.R. China, Department of Oncology, Taishan Medical University Affiliated Zouping Hospital, Zouping, Shandong 256200, P.R. China, Department of Developmental Biology, Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
Published online on: August 13, 2015 https://doi.org/10.3892/or.2015.4202
Pages: 2776-2781

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Abstract

HS1 associated protein X-1 (HAX-1), a substrate of Src family tyrosine kinases, plays a critical role in cell apoptosis. However, its functions in prostate cancer remains unclear. The present study explored the role and mechanism of HAX-1 in cancer cell apoptosis. The mRNA and protein levels of HAX-1 in the prostate cancer cell lines PC-3, VCaP and DU145 were assessed. Cell proliferation, apoptosis and caspase-9 activities were assessed in DU145 after HAX-1 siRNA treatment. The mRNA and protein levels of HAX-1 in prostate cancer cell lines PC-3, VCaP and DU145 were significantly higher than those in the primary prostate epithelial cells, and DU145 possess the highest mRNA and protein levels compared to PC-3 and VCaP. When HAX-1 was knocked down in DU145, cell proliferation was significantly decreased, accompanied by a decrease in Ki67 protein expression. Compared with the control and control siRNA groups, HAX-1 siRNA promoted cell apoptosis and caspase-9 activation in DU145. Furthermore, prostate cancer cells co-transfected with HAX-1 and caspase-9 promoted viability and reduced apoptosis. In contract, co-transfection of caspase-9 and HAX-1 siRNA suppressed the cell viability and enhanced apoptosis. In summary, the present study demonstrated that HAX-1 inhibits cell apoptosis through caspase-9 inactivation.

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1	Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, et al: The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 419:624–629. 2002. View Article : Google Scholar : PubMed/NCBI
2	Tsai HT, Penson DF, Makambi KH, Lynch JH, Van Den Eeden SK and Potosky AL: Efficacy of intermittent androgen deprivation therapy vs conventional continuous androgen deprivation therapy for advanced prostate cancer: A meta-analysis. Urology. 82:327–333. 2013. View Article : Google Scholar : PubMed/NCBI
3	Suzuki Y, Demoliere C, Kitamura D, Takeshita H, Deuschle U and Watanabe T: HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. J Immunol. 158:2736–2744. 1997.PubMed/NCBI
4	Mirmohammadsadegh A, Tartler U, Michel G, Baer A, Walz M, Wolf R, Ruzicka T and Hengge UR: HAX-1, identified by differential display reverse transcription polymerase chain reaction, is overexpressed in lesional psoriasis. J Invest Dermatol. 120:1045–1051. 2003. View Article : Google Scholar : PubMed/NCBI
5	Sharp TV, Wang H-W, Koumi A, Hollyman D, Endo Y, Ye H, Du MQ and Boshoff C: K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. J Virol. 76:802–816. 2002. View Article : Google Scholar
6	Trebinska A, Rembiszewska A, Ciosek K, Ptaszynski K, Rowinski S, Kupryjanczyk J, Siedlecki JA and Grzybowska EA: HAX-1 overexpression, splicing and cellular localization in tumors. BMC Cancer. 10:762010. View Article : Google Scholar : PubMed/NCBI
7	Jing YY, Li XL, Shi Q, Wang ZY, Guo Y, Pan MM, Tian C, Zhu SY, Chen C, Gong HS, et al: A novel PrP partner HS-1 associated protein X-1 (HAX-1) protected the cultured cells against the challenge of H₂O₂. J Mol Neurosci. 45:216–228. 2011. View Article : Google Scholar : PubMed/NCBI
8	Wei XJ, Li SY, Yu B, Chen G, Du JF and Cai HY: Expression of HAX-1 in human colorectal cancer and its clinical significance. Tumour Biol. 35:1411–1415. 2014. View Article : Google Scholar
9	Shaw J and Kirshenbaum LA: HAX-1 represses post-mitochondrial caspase-9 activation and cell death during hypoxia-reoxygenation. Circ Res. 99:336–338. 2006. View Article : Google Scholar : PubMed/NCBI
10	Mahdavi M, Davoodi J, Zali MR and Foroumadi A: Concomitant activation of caspase-9 and down-regulation of IAP proteins as a mechanism of apoptotic death in HepG2, T47D and HCT-116 cells upon exposure to a derivative from 4-aryl-4H-chromenes family. Biomed Pharmacother. 65:175–182. 2011. View Article : Google Scholar : PubMed/NCBI
11	Han Y, Chen YS, Liu Z, Bodyak N, Rigor D, Bisping E, Pu WT and Kang PM: Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circ Res. 99:415–423. 2006. View Article : Google Scholar : PubMed/NCBI
12	Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D and Koeffer HP: Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci USA. 95:8806–8811. 1998. View Article : Google Scholar : PubMed/NCBI
13	Hsieh TC and Wu JM: Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res. 249:109–115. 1999. View Article : Google Scholar : PubMed/NCBI
14	Hsu AL, Ching TT, Wang DS, Song X, Rangnekar VM and Chen CS: The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem. 275:11397–11403. 2000. View Article : Google Scholar
15	Fulda S: Evasion of apoptosis as a cellular stress response in cancer. Int J Cell Biol. 2010:3708352010. View Article : Google Scholar : PubMed/NCBI
16	Plati J, Bucur O and Khosravi-Far R: Apoptotic cell signaling in cancer progression and therapy. Integr Biol Camb. 3:279–296. 2011. View Article : Google Scholar : PubMed/NCBI
17	Akgul C: Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 66:1326–1336. 2009. View Article : Google Scholar
18	Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D and Nagini S: The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. Eur J Pharmacol. 649:84–91. 2010. View Article : Google Scholar : PubMed/NCBI
19	Li WB, Feng J, Geng SM, Zhang PY, Yan XN, Hu G, Zhang CQ and Shi BJ: Induction of apoptosis by Hax-1 siRNA in melanoma cells. Cell Biol Int. 33:548–554. 2009. View Article : Google Scholar : PubMed/NCBI
20	Yap SV, Koontz JM and Kontrogianni-Konstantopoulos A: HAX-1: A family of apoptotic regulators in health and disease. J Cell Physiol. 226:2752–2761. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li M, Tang Y, Zang W, Xuan X, Wang N, Ma Y, Wang Y, Dong Z and Zhao G: Analysis of HAX-1 gene expression in esophageal squamous cell carcinoma. Diagn Pathol. 8:472013. View Article : Google Scholar : PubMed/NCBI
22	Ferri KF and Kroemer G: Organelle-specific initiation of cell death pathways. Nat Cell Biol. 3:E255–E263. 2001. View Article : Google Scholar : PubMed/NCBI
23	Philchenkov A: Caspases: Potential targets for regulating cell death. J Cell Mol Med. 8:432–444. 2004. View Article : Google Scholar : PubMed/NCBI
24	Yin C, Knudson CM, Korsmeyer SJ and Van Dyke T: Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature. 385:637–640. 1997. View Article : Google Scholar : PubMed/NCBI
25	Youle RJ and Strasser A: The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. PubMed/NCBI
26	Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, Yuan J and Thompson CB: Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol. 162:59–69. 2003. View Article : Google Scholar : PubMed/NCBI
27	Deveraux QL and Reed JC: IAP family proteins - suppressors of apoptosis. Genes Dev. 13:239–252. 1999. View Article : Google Scholar : PubMed/NCBI
28	Fadeel B and Grzybowska E: HAX-1: A multifunctional protein with emerging roles in human disease. Biochim Biophys Acta. 1790:1139–1148. 2009. View Article : Google Scholar : PubMed/NCBI
29	Cilenti L, Soundarapandian MM, Kyriazis GA, Stratico V, Singh S, Gupta S, Bonventre JV, Alnemri ES and Zervos AS: Regulation of HAX-1 anti-apoptotic protein by Omi/HtrA2 protease during cell death. J Biol Chem. 279:50295–50301. 2004. View Article : Google Scholar : PubMed/NCBI
30	Gupta K, Thakur VS, Bhaskaran N, Nawab A, Babcook MA, Jackson MW and Gupta S: Green tea polyphenols induce p53-dependent and p53-independent apoptosis in prostate cancer cells through two distinct mechanisms. PLoS One. 7:e525722012. View Article : Google Scholar
31	Martinou JC and Youle RJ: Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 21:92–101. 2011. View Article : Google Scholar : PubMed/NCBI
32	Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E and Boise LH: Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 14:322013. View Article : Google Scholar : PubMed/NCBI
33	Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES and Wang X: Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 91:479–489. 1997. View Article : Google Scholar : PubMed/NCBI
34	Srinivasula SM, Ahmad M, Fernandes-Alnemri T and Alnemri ES: Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Mol Cell. 1:949–957. 1998. View Article : Google Scholar : PubMed/NCBI