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DPP4 Regulates DHCR24-Mediated Cholesterol Biosynthesis to Promote Methotrexate Resistance in Gestational

Weijie Yuan1,2, Wenjing Yong3, Jing Zhu4

  • 1Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China.

Frontiers in Oncology
|December 20, 2021
PubMed

Insights

Dipeptidyl Peptidase 4 (DPP4) promotes methotrexate resistance in gestational trophoblastic neoplastic (GTN) cells by regulating cholesterol biosynthesis. Targeting DPP4 and DHCR24 may sensitize resistant GTN cells to chemotherapy.

Area of Science:

  • Oncology
  • Biochemistry
  • Metabolism

Background:

  • Metabolic reprogramming is crucial for cancer cell adaptation to chemotherapy.
  • Methotrexate (MTX) resistance is a significant challenge in treating gestational trophoblastic neoplastic (GTN) cells.

Purpose of the Study:

  • To investigate the role of Dipeptidyl Peptidase 4 (DPP4) in regulating metabolomic profiles of MTX-resistant GTN cells.
  • To identify downstream effectors and mechanisms by which DPP4 influences MTX resistance.

Main Methods:

  • DPP4 depletion in MTX-resistant GTN cell lines (JAR/MTX, JEG3/MTX).
  • Metabolomic profiling, gene expression analysis, and manipulation of DPP4 and DHCR24.
  • Assessment of cellular cholesterol, reactive oxygen species (ROS), and chemosensitivity.
  • In vitro and in vivo studies using DPP4 inhibitor sitagliptin.

Main Results:

  • DPP4 knockdown altered 80 metabolites, notably impacting cholesterol biosynthesis pathways.
  • DPP4 manipulation affected cellular cholesterol levels and identified DHCR24 as a downstream effector.
  • DHCR24 modulation influenced cholesterol, ROS, and MTX chemosensitivity; its overexpression rescued DPP4-depleted cells.
  • Co-expression of DPP4 and DHCR24 was observed in clinical GTN specimens.
  • Sitagliptin inhibited cholesterol biosynthesis, reduced DHCR24, and enhanced MTX cytotoxicity.

Conclusions:

  • DPP4 promotes MTX resistance in GTN cells via DHCR24-mediated cholesterol biosynthesis.
  • Targeting the DPP4/DHCR24 pathway offers a potential strategy to overcome MTX resistance in GTN.
Keywords:
DHCR24DPP4chemoresistancecholesterolgestational trophoblastic neoplasiamethotrexate

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