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

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.
Yiyan Chen 1,  Min Li 2,  Yanying Yang 1,  Yan Lu 3,  Xiaoying Li 4
Affiliations

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: [email protected].
  • 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: [email protected].
PMID: 36356901 DOI: 10.1016/j.jbc.2022.102678
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.

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