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Cancer Prevention Research
Cancer Prevention Research
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Research Article

Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions

Lynn Vitale-Cross, Alfredo A. Molinolo, Daniel Martin, Rania H. Younis, Takashi Maruyama, Vyomesh Patel, Wanjun Chen, Abraham Schneider and J. Silvio Gutkind
Lynn Vitale-Cross
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Alfredo A. Molinolo
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Daniel Martin
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Rania H. Younis
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Takashi Maruyama
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Vyomesh Patel
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Wanjun Chen
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Abraham Schneider
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J. Silvio Gutkind
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DOI: 10.1158/1940-6207.CAPR-11-0502 Published April 2012
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Received November 7, 2011.
  • Revision received February 24, 2012.
  • Accepted February 28, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Prevention Research: 5 (4)
April 2012
Volume 5, Issue 4
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Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions
Lynn Vitale-Cross, Alfredo A. Molinolo, Daniel Martin, Rania H. Younis, Takashi Maruyama, Vyomesh Patel, Wanjun Chen, Abraham Schneider and J. Silvio Gutkind
Cancer Prev Res April 1 2012 (5) (4) 562-573; DOI: 10.1158/1940-6207.CAPR-11-0502

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Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions
Lynn Vitale-Cross, Alfredo A. Molinolo, Daniel Martin, Rania H. Younis, Takashi Maruyama, Vyomesh Patel, Wanjun Chen, Abraham Schneider and J. Silvio Gutkind
Cancer Prev Res April 1 2012 (5) (4) 562-573; DOI: 10.1158/1940-6207.CAPR-11-0502
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