Abstract
Recent studies suggest that metformin, a widely used antidiabetic agent, may reduce cancer risk and improve prognosis of certain malignancies. However, the mechanisms for the anti-cancer effects of metformin remain uncertain. In this study, we investigated the effects of metformin on human bladder cancer cells and the underlying mechanisms. Metformin significantly inhibited the proliferation and colony formation of 5637 and T24 cells in vitro; specifically, metformin induced an apparent cell cycle arrest in G0/G1 phases, accompanied by a strong decrease of cyclin D1, cyclin-dependent kinase 4 (CDK4), E2F1 and an increase of p21waf-1. Further experiments revealed that metformin activated AMP-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR), the central regulator of protein synthesis and cell growth. Moreover, daily treatment of metformin led to a substantial inhibition of tumor growth in a xenograft model with concomitant decrease in the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and p-mTOR. The in vitro and in vivo results demonstrate that metformin efficiently suppresses the proliferation of bladder cancer cells and suggest that metformin may be a potential therapeutic agent for the treatment of bladder cancer.
Highlights
Bladder cancer is the most common malignancy of the urinary tract and one of the major fatal cancers in adult men [1]
In order to determine whether metformin affected the proliferation of human bladder cancer cells in vitro, we analyzed the effects of the drug on two bladder cancer cell lines: 5637 and T24
Since activation of AMPK has been shown to inhibit the mammalian target of rapamycin (mTOR) pathway, a critical translational pathway for protein synthesis [18], we further examined the effects of metformin on mTOR signaling
Summary
Bladder cancer is the most common malignancy of the urinary tract and one of the major fatal cancers in adult men [1]. Even though bladder cancer is relatively chemotherapy-sensitive, the responses are not typically durable and the majority of these patients experience subsequent disease progression, with a 5-year survival rate of approximately. Epidemiological studies revealed that metformin decreased the incidence of cancer and cancer-related mortality in diabetic patients compared with those treated with other antidiabetic agents [15,16]. A recent study demonstrated that metformin could exert a protective effect on disease recurrence in patients with non-muscle invasive bladder cancer [17], indicating that metformin may be a potential candidate for the development of novel therapeutic agents for bladder cancer. We investigated the effects of metformin on the proliferation of human bladder cancer cells through cell viability MTT assay, cell count assay and colony formation assay. We found that metformin was an efficient inhibitor on the growth of bladder cancer cells
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