title: Inhibition of lung tumorigenesis by metformin is associated with decreased plasma IGF-I and diminished receptor tyrosine kinase signaling.
abstract: Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevented tobacco carcinogen (NNK)-induced lung tumorigenesis in a non-diabetic mouse model, which was associated with decreased IGF-I/insulin receptor signaling but not activation of AMPK in lung tissues, as well as decreased circulating levels of IGF-I and insulin. Here, we used liver IGF-I-deficient (LID) mice to determine the importance of IGF-I in NNK-induced lung tumorigenesis and chemoprevention by metformin. LID mice had decreased lung tumor multiplicity and burden compared with wild-type (WT) mice. Metformin further decreased lung tumorigenesis in LID mice without affecting IGF-I levels, suggesting that metformin can act through IGF-I-independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTK) as well as levels of GTP-bound Ras independently of AMPK. Metformin also diminished plasma levels of several cognate ligands for these RTKs. Tissue distribution studies using [(14)C]-metformin showed that uptake of metformin was high in liver but four-fold lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, indirect effects. Systemic inhibition of circulating growth factors and local RTK signaling are new AMPK-independent mechanisms of action of metformin that could underlie its ability to prevent tobacco carcinogen-induced lung tumorigenesis.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Quinn
authors.forename: Matthew
authors.initials: M
authors.lastname: Dallos
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Ajaikumar B
authors.initials: AB
authors.lastname: Kunnumakkara
authors.forename: Regan M
authors.initials: RM
authors.lastname: Memmott
authors.forename: M Christine
authors.initials: MC
authors.lastname: Hollander
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D018345:Mice, Knockout; D009602:Nitrosamines / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014018:Tissue Distribution
chemical_list: D002273:Carcinogens; D007004:Hypoglycemic Agents; D009602:Nitrosamines; D007334:Insulin-Like Growth Factor I; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D008687:Metformin; D020794:Receptor Protein-Tyrosine Kinases; C548179:Prkaa1 protein, mouse; D055372:AMP-Activated Protein Kinases