GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate.

Abstract

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.

• Authors: Jianjiang Xie, Jianheng Ye, Zhiduan Cai, Yong Luo, Xuejin Zhu, Yulin Deng, Yuanfa Feng, Yingke Liang, Ren Liu, Zhaodong Han, Yuxiang Liang, Yu Zheng, Rujun Mo, Yangjia Zhuo, Yongding Wu, Funeng Jiang, Jianguo Zhu, Chin-Lee Wu, Weide Zhong
• Journal: Cancer research (Cancer Res) Vol. 80 Issue 11 Pg. 2150-2162 (06 01 2020) ISSN: 1538-7445 [Electronic] United States
• PMID: 32179514 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Glycerophosphates
• RNA, Messenger
• Reactive Oxygen Species
• Adenosine Triphosphate
• Metformin
• alpha-glycerophosphoric acid
• Glycerolphosphate Dehydrogenase

Topics

• A549 Cells
• Adenosine Triphosphate (biosynthesis)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Growth Processes (physiology)
• Cell Line, Tumor
• Cell Respiration (physiology)
• Drug Synergism
• Glycerolphosphate Dehydrogenase (biosynthesis, genetics, metabolism)
• Glycerophosphates (metabolism)
• HCT116 Cells
• Heterografts
• Humans
• Male
• Metformin (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• PC-3 Cells
• RNA, Messenger (genetics, metabolism)
• Reactive Oxygen Species (metabolism)