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

1
Department of Otolaryngology-Head and Neck Surgery, University of California, San Diego, CA 92093, USA
2
Hospital Donosita, 20014 Donostia, Gipuzkoa, Spain
3
Veterans Administration Medical Center and Department of Pathology, University of California, San Diego, CA 92092, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(1), 193; https://doi.org/10.3390/ijms20010193
Received: 18 November 2018 / Revised: 18 December 2018 / Accepted: 29 December 2018 / Published: 7 January 2019
(This article belongs to the Section Molecular Oncology)
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. View Full-Text
Keywords: metformin; cancer stem cells; head and neck squamous cell carcinoma; reactive oxygen species metformin; cancer stem cells; head and neck squamous cell carcinoma; reactive oxygen species
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MDPI and ACS Style

Kuo, S.Z.; Honda, C.O.; Li, W.T.; Honda, T.K.; Kim, E.; Altuna, X.; Abhold, E.; Wang-Rodriguez, J.; Ongkeko, W.M. Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma. Int. J. Mol. Sci. 2019, 20, 193. https://doi.org/10.3390/ijms20010193

AMA Style

Kuo SZ, Honda CO, Li WT, Honda TK, Kim E, Altuna X, Abhold E, Wang-Rodriguez J, Ongkeko WM. Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma. International Journal of Molecular Sciences. 2019; 20(1):193. https://doi.org/10.3390/ijms20010193

Chicago/Turabian Style

Kuo, Selena Z., Christine O. Honda, Wei T. Li, Thomas K. Honda, Elizabeth Kim, Xabier Altuna, Eric Abhold, Jessica Wang-Rodriguez, and Weg M. Ongkeko. 2019. "Metformin Results in Diametrically Opposed Effects by Targeting Non-Stem Cancer Cells but Protecting Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma" International Journal of Molecular Sciences 20, no. 1: 193. https://doi.org/10.3390/ijms20010193

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