PT - JOURNAL ARTICLE AU - Vitale-Cross, Lynn AU - Molinolo, Alfredo A. AU - Martin, Daniel AU - Younis, Rania H. AU - Maruyama, Takashi AU - Patel, Vyomesh AU - Chen, Wanjun AU - Schneider, Abraham AU - Gutkind, J. Silvio TI - Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions AID - 10.1158/1940-6207.CAPR-11-0502 DP - 2012 Apr 01 TA - Cancer Prevention Research PG - 562--573 VI - 5 IP - 4 4099 - http://cancerpreventionresearch.aacrjournals.org/content/5/4/562.short 4100 - http://cancerpreventionresearch.aacrjournals.org/content/5/4/562.full SO - Cancer Prev Res (Phila)2012 Apr 01; 5 AB - Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression. Cancer Prev Res; 5(4); 562–73. ©2012 AACR.