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Methionine restriction promotes cisplatin sensitivity of gastric cancer resistant cells by down-regulating circ-CDK13

Lin Xin1, Yong-Hui Zou1, Chen-Xi Liu2

  • 1Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China.

Experimental Cell Research
|November 2, 2024
PubMed
Abstract

Insights

Methionine restriction (MR) enhances cisplatin sensitivity in gastric cancer (GC) by reducing circ-CDK13 levels. This molecular mechanism involves down-regulating eukaryotic initiation factor 4A-III (EIF4A3), offering a new therapeutic strategy for drug-resistant GC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Gastric cancer (GC) poses a significant global health challenge, with drug resistance limiting treatment efficacy.
  • Methionine restriction (MR) is an emerging dietary strategy with potential in cancer therapy.
  • Understanding the molecular mechanisms underlying MR's effects is crucial for optimizing GC treatment.

Purpose of the Study:

  • To investigate the molecular mechanism by which methionine restriction (MR) enhances cisplatin (DDP) sensitivity in drug-resistant gastric cancer (GC) cells.
  • To identify key molecular players, including circRNAs and proteins, involved in MR-mediated sensitization.
  • To validate findings in preclinical models, including patient-derived organoids (PDOs) and mouse models.

Main Methods:

  • Established DDP-resistant GC cell lines, GC patient-derived organoid (PDO) models, and a mouse model of GC.
  • Utilized lentivirus-mediated METase overexpression for MR induction.
  • Assessed cell viability, apoptosis, protein expression (MDR1, MRP1, EIF4A3, METase), and circRNA levels (circ-CDK13) via MTT assay, flow cytometry, Western blotting, and qRT-PCR.

Main Results:

  • Methionine restriction significantly down-regulated circ-CDK13 levels in DDP-resistant GC cells.
  • Overexpression of circ-CDK13 inhibited apoptosis in sensitive GC cells, while its interference promoted apoptosis in drug-resistant cells.
  • MR enhanced DDP sensitivity in resistant GC cells, PDOs, and mice by down-regulating circ-CDK13, mediated by the interaction between EIF4A3 and circ-CDK13.
  • Elevated circ-CDK13 and EIF4A3 expression correlated positively in clinical GC samples.

Conclusions:

  • Methionine restriction inhibits circ-CDK13 levels by down-regulating EIF4A3.
  • This mechanism enhances the sensitivity of drug-resistant gastric cancer cells to cisplatin.
  • The findings highlight a novel therapeutic pathway involving MR, circ-CDK13, and EIF4A3 for overcoming GC chemoresistance.
Keywords:
Circ-CDK13Cisplatin sensitivityEIF4A3Gastric cancerMethionine restriction

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