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

by Yuanchao Gong 1,2,3, Caihong Wang 1,2,3, Yi Jiang 1,2,3, Shaosen Zhang 1,2,3, Shi Feng 1,2,3, Yan Fu 1,2,3 and Yongzhang Luo 1,2,3,*
1
The National Engineering Laboratory for Anti-Tumor Protein Therapeutics, Tsinghua University, Beijing 100084, China
2
Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084, China
3
Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084, China
*
Author to whom correspondence should be addressed.
Cells 2020, 9(1), 144; https://doi.org/10.3390/cells9010144
Received: 8 December 2019 / Revised: 27 December 2019 / Accepted: 2 January 2020 / Published: 7 January 2020
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.
Keywords: metformin; Hsp90α; metastasis; AMPKα1; PKCγ metformin; Hsp90α; metastasis; AMPKα1; PKCγ
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MDPI and ACS Style

Gong, Y.; Wang, C.; Jiang, Y.; Zhang, S.; Feng, S.; Fu, Y.; Luo, Y. Metformin Inhibits Tumor Metastasis through Suppressing Hsp90α Secretion in an AMPKα1-PKCγ Dependent Manner. Cells 2020, 9, 144.

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