Journal
CANCER RESEARCH
Volume 80, Issue 11, Pages 2150-2162Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-2852
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Funding
- National Natural Science Foundation of China [81660426, 81874099, 81600620]
- Guangzhou Municipal Science and Technology [201707010291, 201803040001, 201710010081]
- Science and Technology Project of Bureau of Health in Guangzhou Municipality [20181A010010]
- Fundamental Research Funds for the Central Universities [2018MS18]
- Natural Science Foundation of Guangdong Province [2018A030313668]
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Metformin is an oral drug widely used for the treatment of type 2 diabetes mellitus. Numerous studies have demonstrated the value of metformin in cancer treatment. However, for metformin to elicit effects on cancer often requires a high dosage, and any underlying mechanism for how to improve its inhibitory effects remains unknown. Here, we found that low mRNA expression of glycerol-3-phosphate dehydrogenase 1 (GPD1) may predict a poor response to metformin treatment in 15 cancer cell lines. In vitro and in vivo, metformin treatment alone significantly suppressed cancer cell proliferation, a phenotype enhanced by GPD1 overexpression. Total cellular glycerol-3-phosphate concentration was significantly increased by the combination of GPD1 overexpression and metformin treatment, which suppressed cancer growth via inhibition of mitochondrial function. Eventually, increased reactive oxygen species and mitochondrial structural damage was observed in GPD1-overexpressing cell lines treated with metformin, which may contribute to cell death. In summary, this study demonstrates that GPD1 overexpression enhances the anticancer activity of metformin and that patients with increased GPD1 expression in tumor cells may respond better to metformin therapy. Significance: GPD1 overexpression enhances the anticancer effect of metformin through synergistic inhibition of mitochondrial function, thereby providing new insight into metformin-mediated cancer therapy.
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