Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells

Abstract

// Camille Loubière 1, 2 , Thomas Goiran 1, 2 , Kathiane Laurent 1, 2 , Zied Djabari 1, 2 , Jean-François Tanti 1, 2 , Frédéric Bost 1, 2 1 INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France 2 University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France Correspondence to: Frédéric Bost, e-mail: bost@unice.fr Keywords: prostate cancer, lipogenesis, metformin, cancer metabolism, ATP Received: February 16, 2015      Accepted: February 16, 2015      Published: March 10, 2015 ABSTRACT The deregulation of lipid metabolism is a hallmark of tumor cells, and elevated lipogenesis has been reported in prostate cancer. Metformin, a drug commonly prescribed for type II diabetes, displays antitumor properties. Here, we show that metformin inhibits lipogenesis in several prostate cancer cell lines. In LNCaP cells, this effect parallels the decrease of key lipogenic proteins: ACC (acetyl-CoA carboxylase), FASN (fatty acid synthase) and SREBP1c (sterol regulatory element binding protein-1c), whereas there is no modification in DU145 and PC3 cells. Despite the relatively high level of lipogenic proteins induced by the overexpression of a constitutively active form of SREBP1c or treatment with androgens, metformin is still able to inhibit lipogenesis. Metformin does not alter the concentration of malonyl-CoA (the fatty acid precursor), and it only slightly decreases the NADPH levels, which is a co-factor required for lipogenesis, in LNCaP. Finally, we show that the inhibitory effect of metformin on lipogenesis is primarily due to a cellular energy deficit. Metformin decreases ATP in a dose-dependent manner, and this diminution is significantly correlated with the inhibition of lipogenesis in LNCaP and DU145. Indeed, the effect of metformin is linked to changes in the ATP content rather than the regulation of protein expression. Our results describe a new mechanism of action for metformin on prostate cancer metabolism.