title: Carbon source and myc expression influence the antiproliferative actions of metformin.
abstract: Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound.
authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Shiva
authors.initials: S
authors.lastname: Javeshghani
authors.forename: Mahvash
authors.initials: M
authors.lastname: Zakikhani
authors.forename: Shane
authors.initials: S
authors.lastname: Austin
authors.forename: Miguel
authors.initials: M
authors.lastname: Bazile
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Blouin
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.forename: Julie
authors.initials: J
authors.lastname: St-Pierre
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002244:Carbon / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D002244:Carbon; D000255:Adenosine Triphosphate; D008687:Metformin; D005947:Glucose