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Cancer Res. 2019 Sep 1;79(17):4360-4370. doi: 10.1158/0008-5472.CAN-18-3525. Epub 2019 Jul 10.

Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells.

Author information

1
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
2
Moores Cancer Center, University of California San Diego, La Jolla, California.
3
Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan.
4
International College of Dentistry, Walailak University, Nakhon Si Thammarat, Thailand.
5
Division of Medical Genetics, San Diego School of Medicine, La Jolla, California.
6
Department of Pharmacology, University of California San Diego, La Jolla, California.
7
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. sgutkind@ucsd.edu slippman@ucsd.edu qmchen@scu.edu.cn.
8
Moores Cancer Center, University of California San Diego, La Jolla, California. sgutkind@ucsd.edu slippman@ucsd.edu qmchen@scu.edu.cn.

Abstract

Metformin may reduce the progression of head and neck squamous cell carcinoma (HNSCC); however, whether metformin acts by altering the host metabolism or targets cancer-initiating cells remains poorly understood. This gap in knowledge has prevented the stratification of patient populations who are most likely to benefit from metformin treatment. Here, we explored whether metformin acts directly on HNSCC cells to inhibit aberrant cell growth. To investigate the tumor cell autonomous effects of metformin, we engineered representative HPV- and HPV+ HNSCC cells harboring typical genetic alternations to express the yeast mitochondrial NADH dehydrogenase (NDI1) protein, which is insensitive to metformin. NDI1 expression rescued the inhibitory effects of metformin on mitochondrial complex I, abolished the ability of metformin to activate AMP-activated protein kinase, and inhibited mTOR signaling both in vitro and in vivo, and was sufficient to render metformin ineffective to prevent HNSCC tumor growth. This experimental system provided an opportunity to identify metformin-regulated transcriptional programs linked to cancer cell growth inhibition in the tumor microenvironment. Remarkably, computational analysis of the metformin-induced transcriptome revealed that metformin downregulated gene expression signatures associated with cancer stemness and epithelial-mesenchymal transition, concomitant with increased expression of squamous differentiation genes. These findings support that metformin may act directly on cancer-initiating cells to prevent their progression to HNSCC, which may inform the selection of patients at risk of developing HNSCC in future early-stage clinical trials. SIGNIFICANCE: Metformin's ability to directly target HNSCC-initiating cells instead of exerting cancer preventive activity based solely on its systemic effects may inform the selection of patients in future precision prevention trials.

PMID:
31292160
PMCID:
PMC6726568
[Available on 2020-03-01]
DOI:
10.1158/0008-5472.CAN-18-3525

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