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

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.

Anticancer Activity of Metformin: A Systematic Review of the Literature

“…Deng et al . studied the antiproliferative antisurvival activity of metformin against six triple-negative breast cancer cell lines, and found that metformin induced growth inhibition on all of these cell lines [18].…”

Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

“…3D). It has been proposed that metformin activates AMPK (38,40,42) and in agreement with this, wild type mice have increased phosphorylation of both AMPK and ACC upon metformin treatment. Surprisingly, metformin has the opposite effect in iMSUD mice (Fig.…”

“…4A, Figure S4). Metformin has been shown to promote mitochondrial metabolism via regulation of redox state (33)(34)(35)(36)(37), activation of AMPK (38)(39)(40)(41)(42) and increased the production of lactate (43)(44)(45)(46). Here, metformin was unable to restore intra-tissue lactate or TCA metabolite levels in iMSUD mice unlike in wild type mice, suggesting that BCKDH function is required for metformin action (Fig.…”

Prognostic Implication of pAMPK Immunohistochemical Staining by Subcellular Location and Its Association with SMAD Protein Expression in Clear Cell Renal Cell Carcinoma

“…In agreement with these findings, increased AMPK/pAMPK expression is indicative of favorable survival in patients with carcinomas of the uterine cervix [10], ovary [11], and liver [12] whose tumor cells display cytoplasmic AMPK/pAMPK immunohistochemical (IHC) staining. Conversely, and paradoxically, nuclear pAMPK has been revealed to promote the survival, proliferation, and metastatic capacity of malignant cells under metabolic stress, likely through oncogene activation [13,14]. Recently, Liu et al [14] demonstrated that nuclear pAMPK mediates the proliferation of glucose-deprived human renal cell carcinoma cells, by recruiting pyruvate kinase isozymes M2 and β-catenin.…”

“…Conversely, and paradoxically, nuclear pAMPK has been revealed to promote the survival, proliferation, and metastatic capacity of malignant cells under metabolic stress, likely through oncogene activation [13,14]. Recently, Liu et al [14] demonstrated that nuclear pAMPK mediates the proliferation of glucose-deprived human renal cell carcinoma cells, by recruiting pyruvate kinase isozymes M2 and β-catenin. Although analysis from ccRCC tumor lysates revealed that increased AMPK mRNA and pAMPK are associated with favorable outcomes [1,6], the prognostic significance of pAMPK subcellular location has not yet been investigated in patients with ccRCC.…”