2. Academic Validation
  3. Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase

Metformin sensitises hepatocarcinoma cells to methotrexate by targeting dihydrofolate reductase

  • Cell Death Dis. 2021 Oct 2;12(10):902. doi: 10.1038/s41419-021-04199-1.
Yinghui Wang  # 1,  Hui Lu  # 1,  Linchong Sun 2,  Xin Chen 3 4,  Haoran Wei 1,  Caixia Suo 2,  Junru Feng 1,  Mengqiu Yuan 1,  Shengqi Shen 5,  Weidong Jia 3,  Ying Wang 2,  Huafeng Zhang 6,  Zijun Li 7,  Xiuying Zhong 8,  Ping Gao 9 10
Affiliations

Affiliations

  • 1 Hefei National Laboratory for Physical Sciences at Microscale, The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.
  • 2 Guangzhou First People's Hospital, School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou, China.
  • 3 Anhui Key Laboratory of Hepatopancreatobiliary Surgery, Department of General Surgery, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
  • 4 Suzhou Hospital of Anhui Medical University, Suzhou, China.
  • 5 Guangdong Provincial Institute of Geriatrics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 6 Hefei National Laboratory for Physical Sciences at Microscale, The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China. hzhang22@ustc.edu.cn.
  • 7 Guangdong Provincial Institute of Geriatrics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. zijunli2005@aliyun.com.
  • 8 Guangzhou First People's Hospital, School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou, China. zhongxy@scut.edu.cn.
  • 9 Hefei National Laboratory for Physical Sciences at Microscale, The Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China. pgao2@ustc.edu.cn.
  • 10 Guangzhou First People's Hospital, School of Medicine and Institutes for Life Sciences, South China University of Technology, Guangzhou, China. pgao2@ustc.edu.cn.
  • # Contributed equally.
PMID: 34601503 DOI: 10.1038/s41419-021-04199-1
Abstract

Metformin, the first-line drug for type II diabetes, has recently been considered an Anticancer agent. However, the molecular target and underlying mechanism of metformin's anti-cancer effects remain largely unclear. Herein, we report that metformin treatment increases the sensitivity of hepatocarcinoma cells to methotrexate (MTX) by suppressing the expression of the one-carbon metabolism Enzyme DHFR. We show that the combination of metformin and MTX blocks nucleotide metabolism and thus effectively inhibits cell cycle progression and tumorigenesis. Mechanistically, metformin not only transcriptionally represses DHFR via E2F4 but also promotes lysosomal degradation of the DHFR protein. Notably, metformin dramatically increases the response of patient-derived hepatocarcinoma organoids to MTX without obvious toxicity to organoids derived from normal liver tissue. Taken together, our findings identify an important role for DHFR in the suppressive effects of metformin on therapeutic resistance, thus revealing a therapeutically targetable potential vulnerability in hepatocarcinoma.

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