Metformin targets Clusterin to control lipogenesis and inhibit the growth of bladder cancer cells through SREBP-1c/FASN axis
Abstract
Dear Editor, Metformin, a widely prescribed drug for treating type II diabetes, has shown an important anti-cancer property. However, new launched clinical trials did not achieve such desirable results. One explanation could be that metformin’s anti-cancer mechanisms and precise therapeutic targets remain unclear. To identify potential therapeutic targets of metformin in bladder cancer, we screened differential proteins with metformin treatment in T24 cells by high-throughput protein chip. As shown in Fig. 1a, Clusterin was screened as a target of metformin in bladder cancer. The direct binding of metformin with Clusterin was further confirmed by Surface Plasmon Resonance (SPR) analysis (Fig. 1b). Meanwhile, results from Western blot and RT-PCR showed that treatment with metformin resulted in significant Clusterin downregulation in UMUC3 and J82 cells (Supplementary Fig. S1a, b). Clusterin is a conserved glycoprotein which plays key roles in cellular stress response and survival. As evidenced by its key roles in cancer, Clusterin served as a therapeutic target for fighting tumor growth. We examined the basal level of Clusterin in human bladder cancer cell lines. As shown in Fig. 1c, d, Supplementary Fig. S2a, UMUC3 cells were characterized by significantly highest Clusterin expression while J82 cells were lowest. Interestingly, metformin inhibited cell proliferation, colony formation, migration, and induced apoptosis (Supplementary Fig. S2b–e) greater in higher Clusterin…
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