Back to Search
Start Over
Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells.
- Source :
-
Cancer research [Cancer Res] 2019 Sep 01; Vol. 79 (17), pp. 4360-4370. Date of Electronic Publication: 2019 Jul 10. - Publication Year :
- 2019
-
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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- AMP-Activated Protein Kinases metabolism
Animals
Cell Line, Tumor
Cell Survival drug effects
Electron Transport Complex I antagonists & inhibitors
Electron Transport Complex I genetics
Electron Transport Complex I metabolism
Epithelial-Mesenchymal Transition drug effects
Epithelial-Mesenchymal Transition genetics
Female
Gene Expression Regulation, Neoplastic drug effects
Head and Neck Neoplasms metabolism
Head and Neck Neoplasms pathology
Humans
Mice, Nude
Pyruvates pharmacology
Saccharomyces cerevisiae Proteins genetics
Squamous Cell Carcinoma of Head and Neck metabolism
Squamous Cell Carcinoma of Head and Neck pathology
TOR Serine-Threonine Kinases metabolism
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Head and Neck Neoplasms drug therapy
Metformin pharmacology
Squamous Cell Carcinoma of Head and Neck drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 79
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31292160
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-3525