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Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells

Xianling Guo1, Nannan Ma, Jin Wang

  • 1Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, PR China. guoguo1188@gmail.com

BMC Cancer
|December 19, 2008
PubMed
Abstract

Insights

The p38-MAPK pathway activation increases multidrug resistance (MDR) in cancer cells by upregulating P-glycoprotein (P-gp) and MDR1 gene expression. Inhibiting this pathway enhances chemotherapy sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Multidrug resistance (MDR) is a major challenge in cancer therapy, often linked to P-glycoprotein (P-gp) overexpression due to MDR1 gene upregulation.
  • Gastric adenocarcinoma frequently exhibits MDR1 gene overexpression, contributing to treatment failure.

Purpose of the Study:

  • To investigate the role of the p38-MAPK signaling pathway in vincristine-resistant SGC7901/VCR cells.
  • To determine if p38-MAPK activation influences P-gp expression and subsequent multidrug resistance.

Main Methods:

  • Western blot and RT-PCR were used to detect P-gp and MDR1 RNA.
  • Mitogen-activated protein kinase activity and P-gp function were assessed via Western blot and FACS.
  • AP-1 activity and apoptosis were measured using reporter assays and flow cytometry.

Main Results:

  • Vincristine-resistant cells showed increased MDR1 gene expression and resistance to both P-gp-related and unrelated drugs.
  • Elevated levels of phosphorylated p38-MAPK and AP-1 activity were observed in resistant cells.
  • Inhibiting p38-MAPK with SB202190 decreased AP-1 activity and MDR1 expression, enhancing chemosensitivity.

Conclusions:

  • Activation of the p38-MAPK pathway plays a significant role in mediating multidrug resistance in SGC7901/VCR cells.
  • This pathway influences both P-gp-dependent and P-gp-independent drug resistance mechanisms.

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