2. Academic Validation
  3. A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma

A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma

  • Cell Death Discov. 2021 May 1;7(1):89. doi: 10.1038/s41420-021-00476-2.
Ruogu Pan  # 1,  Zhiqing Yuan  # 1,  Yingbin Liu  # 1,  Xuxu Sun  # 2,  Guiyang Wang  # 1,  Xiaopen Wang  # 1,  Junwen Qu  # 1,  Jian Wang 1,  Jie Yang  # 3,  Yuzheng Zhao  # 4 5,  Yi Yang  # 4 6,  Kewei Li 7
Affiliations

Affiliations

  • 1 Department of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
  • 2 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory forTumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 3 Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory forTumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. yangjieyj@shsmu.edu.cn.
  • 4 Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, Shanghai, China.
  • 5 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
  • 6 CAS Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 7 Department of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China. keweipig@126.com.
  • # Contributed equally.
PMID: 33934113 DOI: 10.1038/s41420-021-00476-2
Abstract

Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor Antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.

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