Metformin Inhibits Progression of Head and Neck Squamous Cell Carcinoma by Acting Directly on Carcinoma-Initiating Cells
| Autor: | Xuefeng Zhang, Huwate Yeerna, Anne N. Murphy, Xingyu Wu, J. Silvio Gutkind, Zhiyong Wang, Scott M. Lippman, Victoria Wu, Panomwat Amornphimoltham, Qianming Chen, Yusuke Goto, Toshinori Ando, Pablo Tamayo |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Epithelial-Mesenchymal Transition Saccharomyces cerevisiae Proteins endocrine system diseases Cell Survival Squamous Differentiation Mice Nude Antineoplastic Agents AMP-Activated Protein Kinases Article Transcriptome 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Medicine Animals Humans Pyruvates Tumor microenvironment Electron Transport Complex I business.industry Squamous Cell Carcinoma of Head and Neck TOR Serine-Threonine Kinases digestive oral and skin physiology Cancer nutritional and metabolic diseases medicine.disease Head and neck squamous-cell carcinoma Xenograft Model Antitumor Assays Metformin Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Cell culture Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer cell Cancer research Female business medicine.drug |
| Zdroj: | Cancer research. 79(17) |
| ISSN: | 1538-7445 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|