Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma

Cancer stem cells (CSCs) have been shown as a distinct population of cancer cells strongly implicated with resistance to conventional chemotherapy. Metformin, the most widely prescribed drug for diabetes, was reported to target cancer stem cells in various cancers. In this study, we sought to determ...

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Bibliographic Details
Published in:	International journal of molecular sciences 2019-01, Vol.20 (1), p.193
Main Authors:	Kuo, Selena Z, Honda, Christine O, Li, Wei Tse, Honda, Thomas K, Kim, Elizabeth, Altuna, Xabier, Abhold, Eric, Wang-Rodriguez, Jessica, Ongkeko, Weg M
Format:	Article
Language:	eng
Subjects:	Antidiabetics Apoptosis Biomarkers, Tumor - metabolism Breast cancer cancer stem cells Cancer therapies Cell death Cell Death - drug effects Cell growth Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Chemotherapy Cisplatin Cisplatin - pharmacology Computer applications Cytoprotection - drug effects Cytotoxicity Dehydrogenases Deoxyribonucleic acid Diabetes DNA Drug dosages Electron Transport Complex III - genetics Electron Transport Complex III - metabolism Gene expression Gene Expression Regulation, Neoplastic - drug effects Head & neck cancer head and neck squamous cell carcinoma Humans Hypotheses Kinases Metformin Metformin - pharmacology Mitochondria Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Population Protein Subunits - metabolism Proteins reactive oxygen species Squamous cell carcinoma Squamous Cell Carcinoma of Head and Neck - genetics Squamous Cell Carcinoma of Head and Neck - pathology Stem cells Studies Tumors
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Summary:	Cancer stem cells (CSCs) have been shown as a distinct population of cancer cells strongly implicated with resistance to conventional chemotherapy. Metformin, the most widely prescribed drug for diabetes, was reported to target cancer stem cells in various cancers. In this study, we sought to determine the effects of metformin on head and neck squamous cell carcinoma (HNSCC). CSCs and non-stem HNSCC cells were treated with metformin and cisplatin alone, and in combination, and cell proliferation levels were measured through MTS assays. Next, potential targets of metformin were explored through computational small molecule binding analysis. In contrast to the reported effects of metformin on CSCs in other cancers, our data suggests that metformin protects HNSCC CSCs against cisplatin in vitro. Treatment with metformin resulted in a dose-dependent induction of the stem cell genes CD44, BMI-1, OCT-4, and NANOG. On the other hand, we observed that metformin successfully decreased the proliferation of non-stem HNSCC cells. Computational drug⁻protein interaction analysis revealed mitochondrial complex III to be a likely target of metformin. Based on our results, we present the novel hypothesis that metformin targets complex III to reduce reactive oxygen species (ROS) levels, leading to the differential effects observed on non-stem cancer cells and CSCs.
ISSN:	1422-0067 1661-6596 1422-0067