Metformin Enhances Cisplatin Cytotoxicity by Suppressing Stat3 Activity Independently of the LKB1-AMPK Pathway.

This study demonstrated a correlation between Stat3 phosphorylation and cisplatin cytotoxicity using AS2 (PC14PE6/AS2)-derived cell lines (AS2/S3C) that contained constitutively active Stat3 plasmids as a model. A Stat3 inhibitor (JSI-124) enhanced the cisplatin sensitivity in AS2 cells, whereas metformin inhibited Stat3 phosphorylation and enhanced cisplatin cytotoxicity. By contrast, another AMPK activator (AICAR) failed to produce these effects. LKB1-AMPK silencing by siRNA or mTOR inhibition by rapamycin or pp242 did not alter the effect of metformin on Stat3 activity suppression, suggesting that metformin can modulate the Stat3 pathway through an LKB1-AMPK and probable MTOR-independent mechanism. Metformin also inhibited cisplatin-induced ROS production and autocrine IL-6 secretion in AS2 cells. Both mechanisms contribute to the ability of metformin to suppress Stat3 activation in cancer cells, which resulted in decreased VEGF secretion by cancer cells. The growth of subcutaneous tumor xenografts was significantly delayed by a combination of cisplatin and metformin. This is the first study to demonstrate that metformin suppresses Stat3 activation via LKB1-AMPK-MTOR independent but ROS and autocrine IL6 production-related pathways. Thus, metformin helps to overcome tumor drug resistance by targeting Stat3. PMID: 23526220 [PubMed - as supplied by publisher]
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Tags: Am J Respir Cell Mol Biol Source Type: research