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Int J Biol Sci 2019; 15(3):617-627. doi:10.7150/ijbs.29689

Research Paper

Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2

Meihan Liu1, Zhuo Zhang2, Hui Wang1, Xiaoliang Chen2✉, Chunxiang Jin1✉

1. Department of Ultrasonography, China-Japan Union Hospital, Jilin University, Changchun, China
2. Department of Urology, China-Japan Union Hospital, Jilin University, Changchun, China

Abstract

Metformin, a common therapeutics for type 2 diabetics, was recently demonstrated to possess antitumor activity in various cancer types. However, its therapy effect in renal cell carcinoma (RCC) still remains controversial. In this study, we found that metformin treatment in RCC cells lead to activation of AMPK, which suppressed the cell proliferation under normal condition, but enhanced cell proliferation under glucose deprivation (GD) condition. Depletion of AMPK by siRNA abolished the proliferation effect of MF under GD condition. Mechanistic investigations revealed that the effect of AMPK on cell proliferation under GD condition is dependent on its nuclear translocation. Moreover, the nuclear AMPK recruits PKM2 and β-Catenin to form a complex, which promotes the transcription of cell proliferation related genes, including CCND1 and c-Myc. Furthermore, depletion of PKM2 or β-Catenin abrogated the proliferative effects of metformin under GD condition. And inhibition of PKM2 also re-sensitized the A498 xenograft in response to metformin treatment. Together, our results suggested that combined of AMPK activation and PKM2 depletion or inhibition can achieve better therapeutic effect for RCC patients.

Keywords: AMPK, renal cancer, PKM2, β-Catenin

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Liu M, Zhang Z, Wang H, Chen X, Jin C. Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2. Int J Biol Sci 2019; 15(3):617-627. doi:10.7150/ijbs.29689. Available from http://www.ijbs.com/v15p0617.htm