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New insight for metformin against bladder cancer.

ABSTRACT: International Agency for Research on Cancer (IARC) estimated that bladder cancer is the ninth most common cancer in the world, with 430,000 new cases and 165,000 deaths in 2012. Bladder cancer represents the fourth most common cancer in men and ninth most common cancer in women. It is the second most prevalent cancer in men 60 years of age or older in United States. Looking further down, continuing advancements in cancer research could potentially offer more choices for clinician and patient with longer survival and better quality of life. Although, bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies; there are limited studies about application of metformin in the management of bladder cancer. Here, I will shed light on the proposed mechanisms of anti-carcinogenic effects of metformin and cohort of these mechanisms with the novel application of metformin as therapy of bladder cancer.

SUBMITTER: El-Arabey AA

PROVIDER: S-EPMC5376285 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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New insight for metformin against bladder cancer.

El-Arabey Amr Ahmed AA

Genes and environment : the official journal of the Japanese Environmental Mutagen Society 20170401

International Agency for Research on Cancer (IARC) estimated that bladder cancer is the ninth most common cancer in the world, with 430,000 new cases and 165,000 deaths in 2012. Bladder cancer represents the fourth most common cancer in men and ninth most common cancer in women. It is the second most prevalent cancer in men 60 years of age or older in United States. Looking further down, continuing advancements in cancer research could potentially offer more choices for clinician and patient wit ...[more]

PMID: 28373897

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Project description:BackgroundMetformin has been reported to function as the anti-tumor inhibiting the growth of different types of cancers, including bladder cancer. But there are few reports on the roles of Yap1, the key molecule of Hippo pathway, in the metformin induced inhibition of bladder cancer (BLCA). We are wondering if the inhibitory effect of metformin on bladder cancer is fulfilled via Yap1 and exploring the related mechanism.MethodsMTS and colony formation assays were used to explore the cellular viabilities and proliferation of BLCA cells challenged by metformin at different concentrations, in vitro. Flow Cytometry (FCM) was used to analyze the cell cycle and the cellular apoptosis of the BLCA cells. Western Blot was performed to detect the expressions of AMPK?, Yap1, CCND1, CCNE1/2 and CDK2/4/6 in the metformin-treated BLCA cell lines. RNAi method was used for the related genetic functional analysis. The relationships among Yap1, TEADs and CCNE1/2 were predicted and evaluated using bioinformatics, dual-luciferase reporter and co-immunoprecipitation (Co-IP) assays. For in vivo experiments, a xenograft model was used to investigate the effects of metformin on the proliferation of BLCA cells. And Immunohistochemistry (IHC) assay was performed to assess the expressions of CCNE1/2 and Yap1 proteins in the tumor tissues from the model.ResultsMetformin could inhibit the proliferation of the BLCA cells via inducing the G1 cell cycle arrest without apoptosis. And metformin upregulated the phosphorylated AMPK? and decreased the expressions of Yap1 and CCND1, CCNE1/2 and CDK4/6. AMPK inhibition by compound C (CC) restored the cell proliferation and the G1 cell cycle arrest induced by metformin, in vivo. Knockdown of YAP1 inhibited the proliferation of BLCA cells and caused the cell cycle arrest at G1 phase by decreasing the expressions of CCNE1/2 and other G1 phase related molecules, which has been restored by the Yap 5SA mutant. Bioinformatics analysis showed that trans-factor TEAD4 was highly expressed and positively associated with the expressions of CCNE1 and CCNE2 in BLCA and only TEAD4 was precipitated by Yap1 in the BLCA cells. Further studies demonstrated that Yap1 positively regulated both CCNE1 and CCNE2 expressions via forming complex with TEAD4. Furthermore, we observed that metformin inhibited the cell proliferation by decreasing the expressions of Yap1 and both CCNE1 and CCNE2 in xenograft model.ConclusionsThe results of our study reveal a new potential regulatory pathway in which metformin inhibits cell proliferation via AMPK?/Yap1/TEAD4/CCNE1/2 axis in BLCA cells, providing new insights into novel molecular therapeutic targets for BLCA.

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New insight for metformin against bladder cancer.

Publications

New insight for metformin against bladder cancer.

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