Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

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 activ...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2012-12, Vol.72 (23), p.6257-6267
Main Authors: JAVESHGHANI, Shiva, ZAKIKHANI, Mahvash, AUSTIN, Shane, BAZILE, Miguel, BLOUIN, Marie-José, TOPISIROVIC, Ivan, ST-PIERRE, Julie, POLLAK, Michael N
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Animals
Antineoplastic agents
Apoptosis
Biological and medical sciences
Carbon - metabolism
Cell Growth Processes - drug effects
Cell Line, Tumor
Colonic Neoplasms - drug therapy
Colonic Neoplasms - genetics
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Glucose - metabolism
Glucose - pharmacology
Glutamine - metabolism
Glutamine - pharmacology
Hypoglycemic Agents - pharmacology
Medical sciences
Metformin - pharmacology
Mice
Mice, Inbred C57BL
Pharmacology. Drug treatments
Phosphorylation
Proto-Oncogene Proteins c-myc - biosynthesis
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Tumors
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-12-2907