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P53 Affects PGC1? Stability Through AKT/GSK-3? to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer.

ABSTRACT: Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1?). Although several studies have confirmed the interaction between p53 and PGC1?, the precise mechanism has not been completely determined in NSCLC. In this study, we investigated the specific signaling between p53 and PGC1? to improve anti-tumor drug effects on NSCLC. We found that low expression of p53 and high expression of PGC1? correlated with shorter survival time of NSCLC patients. In vitro experiments confirmed that NCI-H1299 (p53-null) cells had high levels of PGC1? and were insensitive to cisplatin (CDDP). When PGC1? was knocked down, the sensitivity to cisplatin was increased. Notably, the stability of PGC1? is an important mechanism in its activity regulation. We demonstrated that p53 decreased the stability of PGC1? via the ubiquitin proteasome pathway, which was mediated by protein kinase B (AKT) inhibition and glycogen synthase kinase (GSK-3?) activation. Therefore, p53 may regulate the stability of PGC1? through the AKT/GSK-3? pathway, thus affect the chemosensitivity of NSCLC.

SUBMITTER: Deng X

PROVIDER: S-EPMC7471661 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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p53 Affects PGC1α Stability Through AKT/GSK-3β to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer.

Deng Xinyue X Li Yang Y Gu Shuang S Chen Yingying Y Yu Bingbing B Su Jing J Sun Liankun L Liu Yanan Y

Frontiers in oncology 20200821

Drug resistance greatly limits the therapeutic efficacy of treatment of non-small cell lung cancer (NSCLC). One of the important factors is the dysfunction of tumor suppressor p53. Recent studies have suggested that p53 suppresses tumors by regulating number of mitochondrial proteins, including peroxisome proliferator-activated receptor coactivator (PGC1α). Although several studies have confirmed the interaction between p53 and PGC1α, the precise mechanism has not been completely determined in N ...[more]

PMID: 32974127

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Project description:BackgroundMetastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial-mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified.MethodsThe expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting.ResultsCHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002.ConclusionThese results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

Dataset Information

P53 Affects PGC1? Stability Through AKT/GSK-3? to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer.

Publications

p53 Affects PGC1α Stability Through AKT/GSK-3β to Enhance Cisplatin Sensitivity in Non-Small Cell Lung Cancer.

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