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TIPE1 impairs ovarian tumor growth by promoting caspase-dependent apoptosis.

ABSTRACT: Tumor necrosis factor-?-induced protein 8-like 1 (TIPE1) functions as a tumor suppressor in several types of cancer, including lung and breast cancer. The present study aimed to determine the level of expression and the function of TIPE1 in ovarian cancer. TIPE1 expression was determined in tissue microarrays and ovarian cancer cells, and these data were analyzed to assess the association between TIPE1 expression and prognosis in patients with ovarian cancer. The potential antitumor effects of TIPE1 were investigated in vitro and in a xenograft mouse model. Furthermore, the underlying molecular mechanism by which TIPE1 regulates ovarian cancer growth was determined via flow cytometric analysis, western blotting and rescue experiments. The results of the present study indicated that TIPE1 levels were markedly decreased in ovarian cancer tissues, and its level of expression was associated with a favorable prognosis of patients with ovarian cancer. In addition, ectopic TIPE1 expression significantly impaired A2780 and SKOV3 cell proliferation and colony formation in vitro, which was accompanied by efficient inhibition of xenograft tumor growth in mice. Investigations into the underlying molecular mechanism demonstrated that TIPE1 induced ovarian cancer cell apoptosis by promoting caspase protein expression. Inhibition of caspase-dependent apoptosis by z-VAD blocked TIPE1-mediated inhibition of the proliferation and induction of apoptosis in ovarian cancer cells. Collectively, the results of the present study suggest that TIPE1 may be a potential prognostic predictor and therapeutic target for patients with ovarian cancer.

SUBMITTER: Li T

PROVIDER: S-EPMC7590423 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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TIPE1 impairs ovarian tumor growth by promoting caspase-dependent apoptosis.

Li Tingting T Jia Lei L Deng Yu Y Wang Bo B Quan Song S

Oncology letters 20201015 6

Tumor necrosis factor-α-induced protein 8-like 1 (TIPE1) functions as a tumor suppressor in several types of cancer, including lung and breast cancer. The present study aimed to determine the level of expression and the function of TIPE1 in ovarian cancer. TIPE1 expression was determined in tissue microarrays and ovarian cancer cells, and these data were analyzed to assess the association between TIPE1 expression and prognosis in patients with ovarian cancer. The potential antitumor effects of T ...[more]

PMID: 33133265

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Project description:BackgroundGrowth Arrest and DNA Damage 45γ (GADD45γ) is a member of the DNA damage-inducible gene family which responds to environmental stresses. Apoptosis is a critical mode of renal tubular cell death in nephrotoxin-induced acute kidney injury. In this study, we investigated the role of GADD45γ in renal tubular cell apoptosis induced by nephrotoxic drugs.MethodsPrimary human renal tubular epithelial (HRE) cells were used in this study. To derive stable cell lines in which GADD45γ expression was silenced, HRE cells were transduced with a plasmid encoding GADD45γ-specific shRNA. The recombinant adenovirus containing the GADD45γ gene was synthesized to overexpress GADD45γ protein. Cell death was induced by cisplatin and cyclosporine A (CsA). To prevent apoptotic cell death, pan-caspase inhibitor ZVAD-FMK was used. To prevent non-apoptotic cell death, necrostatin-1 and ferrostatin-1 were used. The degree of apoptosis and necrosis of cultured cells were evaluated by flow cytometry.ResultsExpression of the GADD45γ gene was significantly upregulated in response to treatment with CsA and cisplatin. Apoptosis and necrosis induced by these drugs were significantly reduced by silencing of GADD45γ, and significantly augmented by the overexpression of GADD45γ. The activation of caspase-3 and caspase-7 as well as caspase-9 induced by cisplatin or CsA was reduced by silencing of GADD45γ, and was augmented by the overexpression of GADD45γ, indicating that caspase activation is dependent on the expression of GADD45γ. ZVAD-FMK significantly inhibited apoptosis induced by cisplatin or CsA, indicating a role of caspases in mediating apoptotic cell death. ZVAD-FMK was effective to prevent necrosis as well, indicating that the observed necrosis was a secondary event following apoptosis at least in part.ConclusionsTo our knowledge, this is the first study to show that GADD45γ is required for the caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

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TIPE1 impairs ovarian tumor growth by promoting caspase-dependent apoptosis.

Publications

TIPE1 impairs ovarian tumor growth by promoting caspase-dependent apoptosis.

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