Antidiabetic drug metformin suppresses tumorigenesis through inhibition of mevalonate pathway enzyme HMGCS1

Yiyan Chen; Min Li; Yanying Yang; Yan Lu; Xiaoying Li

doi:10.1016/j.jbc.2022.102678

Antidiabetic drug metformin suppresses tumorigenesis through inhibition of mevalonate pathway enzyme HMGCS1

J Biol Chem. 2022 Dec;298(12):102678. doi: 10.1016/j.jbc.2022.102678. Epub 2022 Nov 8.

Authors

Yiyan Chen¹, Min Li², Yanying Yang¹, Yan Lu³, Xiaoying Li⁴

Affiliations

¹ Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
² Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.
³ Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Metabolism and Regenerative Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: rjluyan@126.com.
⁴ Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. Electronic address: li.xiaoying@zs-hospital.sh.cn.

Abstract

Metformin, an antidiabetic drug, shows some potent antitumor effects. However, the molecular mechanism of metformin in tumor suppression has not been clarified. Here, we provided evidence using in vitro and in vivo data that metformin inhibited mevalonate pathway by downregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), a key enzyme in this pathway. Our results further demonstrated that metformin downregulated HMGCS1 expression through inhibition of transcription factor nuclear factor E2-related factor 2. In addition, we determined that HMGCS1 was highly expressed in human liver and lung cancer tissues and associated with lower survival rates. In summary, our study indicated that metformin suppresses tumorigenesis through inhibition of the nuclear factor E2-related factor 2-HMGCS1 axis, which might be a potential target in cancer prevention and treatment.

Keywords: HMGCS1; MVA; Nrf2; liver cancer; metformin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Transformation, Neoplastic
Humans
Hydroxymethylglutaryl-CoA Synthase / genetics
Hypoglycemic Agents / pharmacology
Metformin* / pharmacology
Mevalonic Acid / metabolism
NF-E2-Related Factor 2 / metabolism

Substances

Metformin
Hypoglycemic Agents
Mevalonic Acid
NF-E2-Related Factor 2
HMGCS1 protein, human
Hydroxymethylglutaryl-CoA Synthase