Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner

Metformin has been documented in epidemiological studies to mitigate tumor progression. Previous reports show that metformin inhibits tumor migration in several cell lines, such as MCF-7 and H1299, but the mechanisms whereby metformin exerts its inhibitory effects on tumor metastasis remain largely unknown. The secreted proteins in cancer cell-derived secretome have been reported to play important roles in tumor metastasis, but whether metformin has an effect on tumor secretome remains unclear. Here we show that metformin inhibits tumor metastasis by suppressing Hsp90 alpha (heat shock protein 90 alpha) secretion. Mass spectrometry (MS) analysis and functional validation identify that eHsp90 alpha (extracellular Hsp90 alpha) is one of the most important secreted proteins for metformin to inhibit tumor cells migration, invasion and metastasis both in vitro and in vivo. Moreover, we find that metformin inhibits Hsp90 alpha secretion in an AMPK alpha 1 dependent manner. Our data elucidate that AMPK alpha 1 (AMP-activated protein kinase alpha 1) decreases the phosphorylation level of Hsp90 alpha by inhibiting the kinase activity of PKC gamma (protein kinase C gamma), which suppresses the membrane translocation and secretion of Hsp90 alpha. Collectively, our results illuminate that metformin inhibits tumor metastasis by suppressing Hsp90 alpha secretion in an AMPK alpha 1 dependent manner.