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

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.

SUBMITTER: Li G

PROVIDER: S-EPMC8524704 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Li Gang G Liao Man M Li Shuang S You Jia J Wang Jun J Lei Wei W Yang Chunlei C Xu Haolun H Xiao He H Chen Haitao H

Experimental and therapeutic medicine 20211001 6

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 mut ...[more]

PMID: 34675993

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Project description:Hyperactivation of the Wingless-type (Wnt)/β-catenin pathway promotes tumor initiation, tumor growth and metastasis in various tissues. Although there is evidence for the involvement of Wnt/β-catenin pathway activation in salivary gland tumors, the precise mechanisms are unknown. Here we report for the first time that downregulation of the Wnt inhibitory factor 1 (WIF1) is a widespread event in salivary gland carcinoma ex-pleomorphic adenoma (CaExPA). We also show that WIF1 downregulation occurs in the CaExPA precursor lesion pleomorphic adenoma (PA) and indicates a higher risk of progression from benign to malignant tumor. Our results demonstrate that diverse mechanisms including WIF1 promoter hypermethylation and loss of heterozygosity contribute to WIF1 downregulation in human salivary gland tumors. In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21. Most importantly, WIF1 significantly diminished the number of salivary gland cancer stem cells and the anchorage-independent cell growth. Consistent with this observation, WIF1 caused a reduction in the expression of pluripotency and stemness markers (OCT4 and c-MYC), as well as adult stem cell self-renewal and multi-lineage differentiation markers, such as WNT3A, TCF4, c-KIT and MYB. Furthermore, WIF1 significantly increased the expression of microRNAs pri-let-7a and pri-miR-200c, negative regulators of stemness and cancer progression. In addition, we show that WIF1 functions as a positive regulator of miR-200c, leading to downregulation of BMI1, ZEB1 and ZEB2, with a consequent increase in downstream targets such as E-cadherin. Our study emphasizes the prognostic and therapeutic potential of WIF1 in human salivary gland CaExPA. Moreover, our findings demonstrate a novel mechanism by which WIF1 regulates cancer stemness and senescence, which might have major implications in the field of cancer biology.

Dataset Information

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

Publications

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

Similar Datasets

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