Abstract
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 Hsp90α (heat shock protein 90α) secretion. Mass spectrometry (MS) analysis and functional validation identify that eHsp90α (extracellular Hsp90α) 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 Hsp90α secretion in an AMPKα1 dependent manner. Our data elucidate that AMPKα1 (AMP-activated protein kinase α1) decreases the phosphorylation level of Hsp90α by inhibiting the kinase activity of PKCγ (protein kinase Cγ), which suppresses the membrane translocation and secretion of Hsp90α. Collectively, our results illuminate that metformin inhibits tumor metastasis by suppressing Hsp90α secretion in an AMPKα1 dependent manner.
Highlights
Metformin is a widely prescribed biguanide derivative used as the first-line therapy for type 2 diabetes
Hsp90α was chosen and hypothesized to modulate the function of metformin for several reasons: (1) the main function of extracellular Hsp90α (eHsp90α) was promoting tumor cells migration, invasion and metastasis, but not tumor cells proliferation. (2) the change of eHsp90α after metformin treatment was relatively large (Ctrl/Met was 3.24). (3) the level of eHsp90α was correlated with the metastasis of multiple cancer types. eHsp90α was detected in concentrated conditioned medium and the results showed that the amount of eHsp90α was decreased after treated with metformin (Figure 1E,F)
We found that the inhibitory effect of metformin on Hsp90α secretion was diminished in AMPKα1
Summary
Metformin is a widely prescribed biguanide derivative used as the first-line therapy for type 2 diabetes. Metformin has been attracting interests due to its anti-tumor effects. Some exciting reports show that metformin inhibits tumor progression alone or in combination with other drugs [2,3,4,5]. Varied mechanisms underlying the anti-tumor effect of metformin have been demonstrated in a number of studies [6,7,8,9,10,11,12,13,14]. Many studies report that metformin can suppress the growth of tumor by leading to apoptosis and autophagy [7,8,9]. Several studies show that metformin can inhibit the epithelial to mesenchymal transition (EMT) process [10,11,12] and regulate the immune system to suppress tumor progression [13,14]
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