SMAC mimetic birinapant inhibits hepatocellular carcinoma growth by activating the cIAP1/TRAF3 signaling pathway

Ding,Jun; Qin,Daming; Zhang,Yong; Li,Qinghe; Li,Yi; Li,Jinmao

doi:10.3892/mmr.2020.10908

SMAC mimetic birinapant inhibits hepatocellular carcinoma growth by activating the cIAP1/TRAF3 signaling pathway

Authors:
- Jun Ding
- Daming Qin
- Yong Zhang
- Qinghe Li
- Yi Li
- Jinmao Li
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Affiliations: Department of Hepatobiliary Surgery, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture (Enshi Clinical College of Wuhan University), Enshi, Hubei 445000, P.R. China, Department of Radiology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture (Enshi Clinical College of Wuhan University), Enshi, Hubei 445000, P.R. China
Published online on: January 3, 2020 https://doi.org/10.3892/mmr.2020.10908
Pages: 1251-1257
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study investigated the effects and molecular mechanism of the second mitochondria‑derived activator of caspase (SMAC) mimetic birinapant on the proliferation and apoptotic rate of liver cancer cells. Western blotting and reverse transcription‑quantitative PCR were used to detect the protein and mRNA expression levels of cellular inhibitor of apoptosis 1 (cIAP1) and tumor necrosis factor receptor‑associated factor 3 (TRAF3) in the liver cancer cell lines Huh7, H22 and HepG2, and the hepatocyte line AML12. Annexin V‑FITC and Transwell assays were used to assess the effect of birinapant pretreatment on the apoptotic rate and invasive ability of liver cancer cells. Lentivirus‑mediated silencing of TRAF3 was performed in liver cancer cells. Western blotting was used to detect the lentivirus silencing efficiency. A subcutaneous hepatocellular carcinoma model was established in nude mice and 15 days after tumor induction the subcutaneous tumors were measured in each group. Immunohistochemistry assays were used to detect the protein expression levels of proliferating cell nuclear antigen and caspase‑3. The results suggested that the expression levels of cIAP1 and TRAF3 were lower in Huh7, H22 and HepG2 cells compared with AML12 cells. Pretreatment with birinapant promoted apoptosis and inhibited invasion of liver cancer cells by activating the cIAP1/TRAF3 axis. Birinapant also promoted apoptosis and inhibited the growth of subcutaneous hepatocellular carcinoma tumors in nude mice. The present results suggested that the SMAC mimetic birinapant may promote apoptosis, and inhibit the proliferation and invasion of liver cancer cells. The molecular mechanism responsible for the effects of birinapant may be related to activation of the cIAP1/TRAF3 signaling pathway by birinapant in liver cancer cells.

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1	Bruix J, Gores GJ and Mazzaferro V: Hepatocellular carcinoma: Clinical frontiers and perspectives. Gut. 63:844–855. 2014. View Article : Google Scholar : PubMed/NCBI
2	Hartke J, Johnson M and Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol. 34:153–159. 2017. View Article : Google Scholar : PubMed/NCBI
3	Boddu P, Carter BZ, Verstovsek S and Pemmaraju N: SMAC mimetics as potential cancer therapeutics in myeloid malignancies. Br J Haematol. 185:219–231. 2019. View Article : Google Scholar : PubMed/NCBI
4	Cossu F, Milani M, Mastrangelo E and Lecis D: Targeting the BIR domains of inhibitor of apoptosis (IAP) proteins in cancer treatment. Comput Struct Biotechnol J. 17:142–150. 2019. View Article : Google Scholar : PubMed/NCBI
5	Pedersen J, LaCasse EC, Seidelin JB, Coskun M and Nielsen OH: Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation. Trends Mol Med. 20:652–665. 2014. View Article : Google Scholar : PubMed/NCBI
6	Chromik J, Safferthal C, Serve H and Fulda S: Smac mimetic primes apoptosis-resistant acute myeloid leukaemia cells for cytarabine-induced cell death by triggering necroptosis. Cancer Lett. 344:101–109. 2014. View Article : Google Scholar : PubMed/NCBI
7	Nikkhoo A, Rostami N, Hojjat-Farsangi M, Azizi G, Yousefi B, Ghalamfarsa G and Jadidi-Niaragh F: Smac mimetics as novel promising modulators of apoptosis in the treatment of breast cancer. J Cell Biochem. 120:9300–9314. 2019. View Article : Google Scholar : PubMed/NCBI
8	Abhari BA, McCarthy N, Le Berre M, Kilcoyne M, Joshi L, Agostinis P and Fulda S: Smac mimetic suppresses tunicamycin-induced apoptosis via resolution of ER stress. Cell Death Dis. 10:1552019. View Article : Google Scholar : PubMed/NCBI
9	Gerges S, Rohde K and Fulda S: Cotreatment with Smac mimetics and demethylating agents induces both apoptotic and necroptotic cell death pathways in acute lymphoblastic leukemia cells. Cancer Lett. 375:127–132. 2016. View Article : Google Scholar : PubMed/NCBI
10	Brumatti G, Ma C, Lalaoui N, Nguyen NY, Navarro M, Tanzer MC, Richmond J, Ghisi M, Salmon JM, Silke N, et al: The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci Transl Med. 8:339ra692016. View Article : Google Scholar : PubMed/NCBI
11	Shu X, Zhu Z, Cao D, Zheng L, Wang F, Pei H, Wen J, Yang J, Li D, Bai P, et al: PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy. Colloids Surf B Biointerfaces. 182:1103562019. View Article : Google Scholar : PubMed/NCBI
12	Liu H, Liao R, He K, Zhu X, Li P and Gong J: The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells. Immunol Lett. 85:79–83. 2017. View Article : Google Scholar
13	Ho PC, Tsui YC, Feng X, Greaves DR and Wei LN: NF-κB-mediated degradation of the coactivator RIP140 regulates inflammatory responses and contributes to endotoxin tolerance. Nat Immunol. 13:379–386. 2012. View Article : Google Scholar : PubMed/NCBI
14	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
15	Liu Z, Mar KB, Hanners NW, Perelman SS, Kanchwala M, Xing C, Schoggins JW and Alto NM: A NIK-SIX signalling axis controls inflammation by targeted silencing of non-canonical NF-κB. Nature. 68:249–253. 2019. View Article : Google Scholar
16	Mi L, Zhou Y, Wu D, Tao Q, Wang X, Zhu H, Gao X, Wang J, Ling R, Deng J, et al: ACSS2/AMPK/PCNA pathway-driven proliferation and chemoresistance of esophageal squamous carcinoma cells under nutrient stress. Mol Med Rep. 20:5286–5296. 2019.PubMed/NCBI
17	Sato Y, Yoshino H, Kazama Y and Kashiwakura I: Involvement of caspase-8 in apoptosis enhancement by cotreatment with retinoic acid-inducible gene-I-like receptor agonist and ionizing radiation in human non-small cell lung cancer. Mol Med Rep. 18:5286–5294. 2018.PubMed/NCBI
18	Razmkhah M, Abtahi S and Ghaderi A: Mesenchymal stem cells, immune cells and tumor cells crosstalk: A sinister triangle in the tumor microenvironment. Curr Stem Cell Res Ther. 14:43–51. 2019. View Article : Google Scholar : PubMed/NCBI
19	Jin Y, Meng X, Qiu Z, Su Y, Yu P and Qu P: Anti-tumor and anti-metastatic roles of cordycepin, one bioactive compound of Cordyceps militaris. Saudi J Biol Sci. 25:991–995. 2018. View Article : Google Scholar : PubMed/NCBI
20	Verhagen AM and Vaux DL: Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis. 7:163–166. 2002. View Article : Google Scholar : PubMed/NCBI
21	Soung YH, Park WS, Nam SW, Lee JY, Yoo NJ and Lee SH: SMAC/DIABLO mutation is uncommon in gastric and colorectal carcinomas. Pathology. 38:85–87. 2016. View Article : Google Scholar
22	Cekay MJ, Roesler S, Frank T, Knuth AK, Eckhardt I and Fulda S: Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines. Cancer Lett. 410:228–237. 2017. View Article : Google Scholar : PubMed/NCBI
23	Bhatti IA, Abhari BA and Fulda S: Identification of a synergistic combination of Smac mimetic and Bortezomib to trigger cell death in B-cell non-Hodgkin lymphoma cells. Cancer Lett. 405:63–72. 2017. View Article : Google Scholar : PubMed/NCBI
24	Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA and Karin M: Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 11:70–75. 2010. View Article : Google Scholar : PubMed/NCBI
25	Lin WW, Hostager BS and Bishop GA: TRAF3, ubiquitination, and B-lymphocyte regulation. Immunol Rev. 266:46–55. 2015. View Article : Google Scholar : PubMed/NCBI
26	Wen J, Bai H, Chen N, Zhang W, Zhu X, Li P and Gong J: USP25 promotes endotoxin tolerance via suppressing K48-linked ubiquitination and degradation of TRAF3 in Kupffer cells. Mol Immunol. 106:53–62. 2019. View Article : Google Scholar : PubMed/NCBI
27	Guan K, Wei C, Zheng Z, Song T, Wu F, Zhang Y, Cao Y, Ma S, Chen W, Xu Q, et al: MAVS promotes inflammasome activation by targeting ASC for K63-linked ubiquitination via the E3 ligase TRAF3. J Immunol. 194:4880–4890. 2015. View Article : Google Scholar : PubMed/NCBI
28	Muro I, Fang G, Gardella KA, Mahajan IM and Wright CW: The TRAF3 adaptor protein drives proliferation of anaplastic large cell lymphoma cells by regulating multiple signaling pathways. Cell Cycle. 13:1918–1927. 2014. View Article : Google Scholar : PubMed/NCBI
29	Eytan DF, Snow GE, Carlson S, Derakhshan A, Saleh A, Schiltz S, Cheng H, Mohan S, Cornelius S, Coupar J, et al: SMAC Mimetic birinapant plus radiation eradicates human head and neck cancers with genomic amplifications of cell death genes FADD and BIRC2. Cancer Res. 76:5442–5454. 2016. View Article : Google Scholar : PubMed/NCBI
30	Zhu X, Shen X, Qu J, Straubinger RM and Jusko WJ: Multi-scale network model supported by proteomics for analysis of combined gemcitabine and birinapant effects in pancreatic cancer cells. CPT Pharmacometrics Syst Pharmacol. 7:549–561. 2018. View Article : Google Scholar : PubMed/NCBI