Inhibition of cIAP1 in the effective suppression of chemotherapy‑resistant hepatoblastoma

Tsukada,Ryo; Nomura,Motonari; Ueno,Takehisa; Okuyama,Hiroomi

doi:10.3892/or.2022.8290

Inhibition of cIAP1 in the effective suppression of chemotherapy‑resistant hepatoblastoma

Authors:
- Ryo Tsukada
- Motonari Nomura
- Takehisa Ueno
- Hiroomi Okuyama
View Affiliations

Affiliations: Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565‑0871, Japan
Published online on: February 22, 2022 https://doi.org/10.3892/or.2022.8290
Article Number: 79

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

Cellular inhibitor of apoptosis protein‑1 (cIAP1) is a key regulator of programmed cell death and is known to be associated with chemotherapeutic resistance. The present study aimed to investigate the antitumor efficacy of birinapant, a novel selective inhibitor of cIAP1, against cisplatin (CDDP)‑resistant hepatoblastoma (HB) cells. Western blot analysis was used to investigate the antitumor effect of birinapant on cIAP1 expression in Huh6 cells at the protein level. A WST‑8 assay was performed to evaluate the tumor growth inhibitory effect of birinapant on the human HB cell lines, Huh6 and HepG2. Huh6 cells were exposed to CDDP and/or birinapant in order to confirm tumor growth inhibition. The antitumor efficacy of birinapant plus CDDP combination therapy was significantly higher than that of CDDP monotherapy in a dose‑dependent manner (P=0.035). The study also investigated the antitumor efficacy of birinapant plus CDDP combination therapy in an established xenograft model of SCID mice. Compared with CDDP monotherapy, birinapant combined with CDDP showed better inhibition of tumor growth (P=0.121). It was observed that the mRNA expression of cIAP1 in tumors was significantly enriched in the CDDP monotherapy group compared with that in the untreated group. Furthermore, immunohistochemical staining was performed to compare cIAP1 expression in pre‑ and post‑chemotherapy specimens in patients with HB, and a significant increase was observed in the post‑chemotherapy specimens (P<0.001). CDDP‑resistant Huh6 (Huh6‑CDDP^R) cells were also established following repeated exposure to CDDP. Birinapant was substantially more effective against the Huh6‑CDDP^R cells than against the Huh6 wild‑type cells. Taken together, these findings suggest that repeated exposure to CDDP enhances cIAP1 expression in HB cells and that birinapant is a promising therapeutic drug for CDDP‑resistant HB.

View Figures

View References

1	Lim IIP, Bondoc AJ, Geller JI and Tiao GM: Hepatoblastoma-the evolution of biology, surgery, and transplantation. Children (Basel). 6:12018.PubMed/NCBI
2	Aronson DC, Czauderna P, Maibach R, Perilongo G and Morland B: The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. J Indian Assoc Pediatr Surg. 19:201–207. 2014. View Article : Google Scholar : PubMed/NCBI
3	Zsiros J, Brugieres L, Brock P, Roebuck D, Maibach R, Zimmermann A, Childs M, Pariente D, Laithier V, Otte JB, et al: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study. Lancet Oncol. 14:834–842. 2013. View Article : Google Scholar : PubMed/NCBI
4	Schimmer AD: Inhibitor of apoptosis proteins: Translating basic knowledge into clinical practice. Cancer Res. 64:7183–7190. 2004. View Article : Google Scholar : PubMed/NCBI
5	Finlay D, Teriete P, Vamos M, Cosford NDP and Vuori K: Inducing death in tumor cells: Roles of the inhibitor of apoptosis proteins. F1000Res. 6:5872017. View Article : Google Scholar : PubMed/NCBI
6	Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, LaPorte MG, Rippin SR, et al: Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models. Mol Cancer Ther. 13:867–879. 2014. View Article : Google Scholar : PubMed/NCBI
7	Dynek JN and Vucic D: Antagonists of IAP proteins as cancer therapeutics. Cancer Lett. 332:206–214. 2013. View Article : Google Scholar : PubMed/NCBI
8	Nachmias B, Ashhab Y and Ben-Yehuda D: The inhibitor of apoptosis protein family (IAPs): An emerging therapeutic target in cancer. Semin Cancer Biol. 14:231–243. 2004. View Article : Google Scholar : PubMed/NCBI
9	Camp JG, Sekine K, Gerber T, Loeffler-Wirth H, Binder H, Gac M, Kanton S, Kageyama J, Damm G, Seehofer D, et al: Multilineage communication regulates human liver bud development from pluripotency. Nature. 546:533–538. 2017. View Article : Google Scholar : PubMed/NCBI
10	Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T and Reed JC: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 58:5315–5320. 1998.PubMed/NCBI
11	Hunter AM, LaCasse EC and Korneluk RG: The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis. 12:1543–1568. 2007. View Article : Google Scholar : PubMed/NCBI
12	Amaravadi RK, Schilder RJ, Martin LP, Levin M, Graham MA, Weng DE and Adjei AA: A phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol Cancer Ther. 14:2569–2575. 2015. View Article : Google Scholar : PubMed/NCBI
13	Noonan AM, Bunch KP, Chen JQ, Herrmann MA, Lee JM, Kohn EC, O'Sullivan CC, Jordan E, Houston N, Takebe N, et al: Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer. Cancer. 122:588–597. 2016. View Article : Google Scholar : PubMed/NCBI
14	Allensworth JL, Sauer SJ, Lyerly HK, Morse MA and Devi GR: Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism. Breast Cancer Res Treat. 137:359–371. 2013. View Article : Google Scholar : PubMed/NCBI
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Stucchi G, Battevi N, Cairoli S and Consonni D: The prevalence of musculoskeletal disorders in the retail sector: An Italian cross sectional study on 3,380 workers. Med Lav. 107:251–262. 2016.PubMed/NCBI
17	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
18	LaCasse EC, Baird S, Korneluk RG and MacKenzie AE: The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene. 17:3247–3259. 1998. View Article : Google Scholar : PubMed/NCBI
19	Wallace C and Unger S: A matter of life and death. Commun Int. 26:341999.
20	Krajewska M, Krajewski S, Banares S, Huang X, Turner B, Bubendorf L, Kallioniemi OP, Shabaik A, Vitiello A, Peehl D, et al: Elevated expression of inhibitor of apoptosis proteins in prostate cancer. Clin Cancer Res. 9:4914–4925. 2003.PubMed/NCBI
21	Tanimoto T, Tsuda H, Imazeki N, Ohno Y, Imoto I, Inazawa J and Matsubara O: Nuclear expression of cIAP-1, an apoptosis inhibiting protein, predicts lymph node metastasis and poor patient prognosis in head and neck squamous cell carcinomas. Cancer Lett. 224:141–151. 2005. View Article : Google Scholar : PubMed/NCBI
22	Nakagawa Y, Abe S, Kurata M, Hasegawa M, Yamamoto K, Inoue M, Takemura T, Suzuki K and Kitagawa M: IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am J Hematol. 81:824–831. 2006. View Article : Google Scholar : PubMed/NCBI
23	Wu HH, Wu JY, Cheng YW, Chen CY, Lee MC, Goan YG and Lee H: cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer. Clin Cancer Res. 16:5200–5210. 2010. View Article : Google Scholar : PubMed/NCBI
24	Miura K, Karasawa H and Sasaki I: cIAP2 as a therapeutic target in colorectal cancer and other malignancies. Expert Opin Ther Targets. 13:1333–1345. 2009. View Article : Google Scholar : PubMed/NCBI
25	Nagata M, Nakayama H, Tanaka T, Yoshida R, Yoshitake Y, Fukuma D, Kawahara K, Nakagawa Y, Ota K, Hiraki A and Shinohara M: Overexpression of cIAP2 contributes to 5-FU resistance and a poor prognosis in oral squamous cell carcinoma. Br J Cancer. 105:1322–1330. 2011. View Article : Google Scholar : PubMed/NCBI
26	Lopes RB, Gangeswaran R, McNeish IA, Wang Y and Lemoine NR: Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer. 120:2344–2352. 2007. View Article : Google Scholar : PubMed/NCBI
27	Lee SK, Kim SB, Kim JS, Moon CH, Han MS, Lee BJ, Chung DK, Min YJ, Park JH, Choi DH, et al: Butyrate response factor 1 enhances cisplatin sensitivity in human head and neck squamous cell carcinoma cell lines. Int J Cancer. 117:32–40. 2005. View Article : Google Scholar : PubMed/NCBI
28	Ebert G, Lopaticki S, O'Neill MT, Steel RWJ, Doerflinger M, Rajasekaran P, Yang ASP, Erickson S, Ioannidis L, Arandjelovic P, et al: Targeting the extrinsic pathway of hepatocyte apoptosis promotes clearance of plasmodium liver infection. Cell Rep. 30:4343–4354.e4. 2020. View Article : Google Scholar : PubMed/NCBI