title: Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells.
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.
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Loubière
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Goiran
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Kathiane
authors.initials: K
authors.lastname: Laurent
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Zied
authors.initials: Z
authors.lastname: Djabari
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
authors.affiliation: INSERM, C3M, U1065, Team Cellular and Molecular Physiopathology of Diabetes and Obesity, Nice 06200, France.|University of Nice Sophia Antipolis, C3M, U1065, Nice 06200, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D009249:NADP / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D008316:Malonyl Coenzyme A; D009249:NADP; D000255:Adenosine Triphosphate; D008687:Metformin; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D000103:Acetyl-CoA Carboxylase
keywords: ATP; cancer metabolism; lipogenesis; metformin; prostate cancer