Abstract
Abstract Metformin is the most commonly prescribed drug for type II diabetes and is associated with decreased cancer risk. Previously, we showed that metformin prevents tobacco carcinogen (NNK)-induced lung tumorigenesis in mice, which was associated with decreased IGF-I/insulin receptor signaling in lung tissues, decreased circulating levels of insulin-like growth factor-1 (IGF-1) and insulin, but not activation of AMPK. Here, we used liver-IGF-1-deficient (LID) mice to determine the importance of IGF-1 in tobacco carcinogen-induced lung tumorigenesis and chemoprevention by metformin. NNK-induced lung tumor multiplicity and burden were significantly decreased in LID mice, identifying IGF-1 as an oncogenic factor. Metformin further decreased lung tumorigenesis in LID mice, suggesting that metformin acts through IGF-1-independent mechanisms. In lung tissues, metformin decreased phosphorylation of multiple receptor tyrosine kinases (RTKs), independent of AMP-activated protein kinase (AMPK). Tissue distribution of [14C]-metformin was high in liver but much lower in lungs, suggesting that the suppression of RTK activation by metformin occurs predominantly via systemic, cell-autonomous effects. Indeed, metformin decreased plasma levels of several cognate ligands for these RTK. These results identify systemic inhibition of RTK signaling as a new mechanism of action for metformin that could underlie its chemopreventive effects. This abstract is also presented as Poster B60. Citation Format: Brendan J. Quinn, Matthew Dallos, Hiroshi Kitagawa, Ajaikumar B. Kunnumakkara, Regan M. Memmott, Joell J. Gills, M. Christine Hollander, Phillip A. Dennis. Systemic inhibition of receptor tyrosine kinase signaling by metformin. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PR-01.
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