Downregulation of inhibitor of apoptosis protein induces apoptosis and suppresses stemness maintenance in testicular teratoma

Li,Gang; Liao,Man; Li,Shuang; You,Jia; Wang,Jun; Lei,Wei; Yang,Chunlei; Xu,Haolun; Xiao,He; Chen,Haitao

doi:10.3892/etm.2021.10835

Downregulation of inhibitor of apoptosis protein induces apoptosis and suppresses stemness maintenance in testicular teratoma

Authors:
- Gang Li
- Man Liao
- Shuang Li
- Jia You
- Jun Wang
- Wei Lei
- Chunlei Yang
- Haolun Xu
- He Xiao
- Haitao Chen
View Affiliations

Affiliations: Department of Urology, Wuhan Children's Hospital, Wuhan, Hubei 430016, P.R. China
Published online on: October 1, 2021 https://doi.org/10.3892/etm.2021.10835
Article Number: 1399
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Inhibitors of apoptosis (IAPs) are a family of cell death inhibitors found in viruses and metazoans that physically interact with a variety of pro‑apoptotic proteins and inhibit apoptosis induced by diverse stimuli. Melanoma IAP (ML‑IAP) is a potent anti‑apoptotic protein that is strongly upregulated in melanoma and confers protection against a variety of pro‑apoptotic stimuli. In the present study, it was revealed that ML‑IAP was expressed at high levels in testicular teratoma. Deletion and mutational analysis demonstrated that ML‑IAP silencing significantly decreased P19 cell proliferation while inducing cell cycle arrest and apoptosis. ML‑IAP knockdown significantly induced caspase‑3/8/9‑mediated apoptosis in P19 cells. In addition, metabolism and stemness maintenance in P19 cells were suppressed by ML‑IAP knockdown. These results indicated that ML‑IAP silencing is a powerful inducer of apoptosis mediated by cell death receptors and may function as a direct activator of downstream effector caspases.

View Figures

View References

1	Karmazyn B, Weatherly DL, Lehnert SJ, Cain MP, Fan R, Jennings SG, Ouyang F and Kaefer M: Characteristics of testicular tumors in prepubertal children (age 5-12 years). J Pediatr Urol. 14:259.e1–259.e6. 2018.PubMed/NCBI View Article : Google Scholar
2	Juliachs M, Muñoz C, Moutinho CA, Vidal A, Condom E, Esteller M, Graupera M, Casanovas O, Germà JR, Villanueva A and Viñals F: The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors. Clin Cancer Res. 20:658–667. 2014.PubMed/NCBI View Article : Google Scholar
3	Wang X, Xu S, Tang D, Li M, Wu D and Huang Y: Prepubertal testicular and paratesticular tumors in China: A single-center experience over a 10-year period. J Pediatr Surg. 47:1576–1580. 2012.PubMed/NCBI View Article : Google Scholar
4	Berney DM, Lu YJ, Shamash J and Idrees M: Postchemotherapy changes in testicular germ cell tumours: Biology and morphology. Histopathology. 70:26–39. 2017.PubMed/NCBI View Article : Google Scholar
5	Rathore R, McCallum JE, Varghese E, Florea AM and Büsselberg D: Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis. 22:898–919. 2017.PubMed/NCBI View Article : Google Scholar
6	Kocab AJ and Duckett CS: Inhibitor of apoptosis proteins as intracellular signaling intermediates. FEBS J. 283:221–231. 2016.PubMed/NCBI View Article : Google Scholar
7	Mohamed MS, Bishr MK, Almutairi FM and Ali AG: Inhibitors of apoptosis: Clinical implications in cancer. Apoptosis. 22:1487–1509. 2017.PubMed/NCBI View Article : Google Scholar
8	Fulda S: Molecular pathways: Targeting inhibitor of apoptosis proteins in cancer-from molecular mechanism to therapeutic application. Clin Cancer Res. 20:289–295. 2014.PubMed/NCBI View Article : Google Scholar
9	Rada M, Nallanthighal S, Cha J, Ryan K, Sage J, Eldred C, Ullo M, Orsulic S and Cheon DJ: Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer. Oncogene. 37:4809–4820. 2018.PubMed/NCBI View Article : Google Scholar
10	Checinska A, Hoogeland B, Rodriguez JA, Giaccone G and Kruyt FA: Role of XIAP in inhibiting cisplatin-induced caspase activation in non-small cell lung cancer cells: A small molecule Smac mimic sensitizes for chemotherapy-induced apoptosis by enhancing caspase-3 activation. Exp Cell Res. 313:1215–1224. 2007.PubMed/NCBI View Article : Google Scholar
11	Dawood S, Austin L and Cristofanilli M: Cancer stem cells: Implications for cancer therapy. Oncology (Williston Park). 28:1101–1107, 1110. 2014.PubMed/NCBI
12	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006.PubMed/NCBI View Article : Google Scholar
13	Trosko JE: Evolution of energy metabolism, stem cells and cancer stem cells: How the Warburg and Barker hypothesis might be linked. BMC Proc. 7 (Suppl 2)(K8)2013.PubMed/NCBI View Article : Google Scholar
14	Pacini N and Borziani F: Cancer stem cell theory and the warburg effect, two sides of the same coin? Int J Mol Sci. 15:8893–8930. 2014.PubMed/NCBI View Article : Google Scholar
15	Vaupel P, Schmidberger H and Mayer A: The Warburg effect: Essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol. 95:912–919. 2019.PubMed/NCBI View Article : Google Scholar
16	Schwartz L, Supuran CT and Alfarouk KO: The warburg effect and the hallmarks of cancer. Anticancer Agents Med Chem. 17:164–170. 2017.PubMed/NCBI View Article : Google Scholar
17	Ji J, Yu Y, Li ZL, Chen MY, Deng R, Huang X, Wang GF, Zhang MX, Yang Q, Ravichandran S, et al: XIAP limits autophagic degradation of Sox2 and is a therapeutic target in nasopharyngeal carcinoma stem cells. Theranostics. 8:1494–1510. 2018.PubMed/NCBI View Article : Google Scholar
18	Ausserlechner MJ and Hagenbuchner J: Mitochondrial survivin-an Achilles' heel in cancer chemoresistance. Mol Cell Oncol. 3(e1076589)2015.PubMed/NCBI View Article : Google Scholar
19	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.PubMed/NCBI View Article : Google Scholar
20	Galli UM, Sauter M, Lecher B, Maurer S, Herbst H, Roemer K and Mueller-Lantzsch N: Human endogenous retrovirus rec interferes with germ cell development in mice and may cause carcinoma in situ, the predecessor lesion of germ cell tumors. Oncogene. 24:3223–3228. 2005.PubMed/NCBI View Article : Google Scholar
21	Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS and Dixit VM: ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol. 10:1359–1366. 2000.PubMed/NCBI View Article : Google Scholar
22	Ashhab Y, Alian A, Polliack A, Panet A and Ben Yehuda D: Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett. 495:56–60. 2001.PubMed/NCBI View Article : Google Scholar
23	Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC: IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17:2215–2223. 1998.PubMed/NCBI View Article : Google Scholar
24	Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC: The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16:6914–6925. 1997.PubMed/NCBI View Article : Google Scholar
25	Green DR and Evan GI: A matter of life and death. Cancer Cell. 1:19–30. 2002.PubMed/NCBI View Article : Google Scholar
26	Epstein T, Gatenby RA and Brown JS: The Warburg effect as an adaptation of cancer cells to rapid fluctuations in energy demand. PLoS One. 12(e0185085)2017.PubMed/NCBI View Article : Google Scholar
27	Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM and Cantley LC: Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 329:1492–1499. 2010.PubMed/NCBI View Article : Google Scholar
28	Wang YD, Li SJ and Liao JX: Inhibition of glucose transporter 1 (GLUT1) chemosensitized head and neck cancer cells to cisplatin. Technol Cancer Res Treat. 12:525–535. 2013.PubMed/NCBI View Article : Google Scholar
29	Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat Rev Cancer. 8:755–768. 2008.PubMed/NCBI View Article : Google Scholar
30	Lu Y, Zhu H, Shan H, Lu J, Chang X, Li X, Lu J, Fan X, Zhu S, Wang Y, et al: Knockdown of Oct4 and Nanog expression inhibits the stemness of pancreatic cancer cells. Cancer Lett. 340:113–123. 2013.PubMed/NCBI View Article : Google Scholar
31	Santini R, Pietrobono S, Pandolfi S, Montagnani V, D'Amico M, Penachioni JY, Vinci MC, Borgognoni L and Stecca B: SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells. Oncogene. 33:4697–4708. 2014.PubMed/NCBI View Article : Google Scholar