Metformin Inhibits Prostate Cancer Progression via Regulation of the AKT/mTOR Signaling Pathway

Objective  To investigate the effects of metformin on the proliferation, migration, and invasion of prostate cancer cells, and to determine whether its antitumor effects are mediated by regulation of human antigen R (HuR) and the AKT/mammalian target of rapamycin (mTOR) signaling pathway.

Methods  Human prostate cancer cell lines PC3 and 22RV1 were used as the research models and were treated with metformin. HuR knockdown and overexpression experiments were performed to further verify the underlying mechanism. Cell proliferation was assessed using the cell counting kit-8 (CCK-8) assay. Cell migration and invasion were evaluated by Transwell assays. The expression levels of HuR and AKT/mTOR pathway-related proteins were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.

Results  Metformin treatment reduced the proliferation, migration, and invasion abilities of PC3 and 22RV1 cells, and inhibited the expression of proteins associated with the AKT/mTOR signaling pathway (P < 0.05). HuR knockdown also decreased the proliferation, migration, and invasion abilities of prostate cancer cells and inhibited AKT/mTOR pathway activity. In contrast, HuR overexpression partially attenuated the inhibitory effects of metformin on the malignant biological behaviors of prostate cancer cells and its inhibitory effects on the AKT/mTOR signaling pathway. In addition, metformin downregulated HuR mRNA and protein expression levels in PC3 and 22RV1 cells in a concentration-dependent manner (P < 0.01).

Conclusion  Metformin may inhibit the activation of the AKT/mTOR signaling pathway by downregulating HuR expression, thereby reducing the proliferation, migration, and invasion of prostate cancer cells.