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Src/caveolin-1-regulated EGFR activation antagonizes TRAIL-induced apoptosis in gastric cancer cells

Ling Xu1, Xiujuan Qu1, Heming Li1

  • 1Department of Medical Oncology, The First Hospital of China Medical University, Heping, Shenyang 110001, P.R. China.

Oncology Reports
|May 21, 2014
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in gastric cancer involves epidermal growth factor receptor (EGFR) activation. Caveolin-1 and Src kinase mediate this EGFR activation, hindering TRAIL-induced apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Gastric cancer cells exhibit resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
  • Epidermal growth factor receptor (EGFR) activation, regulated by lipid rafts, has been identified as an antagonist to TRAIL-induced apoptosis.

Purpose of the Study:

  • To investigate the role of caveolin-1 in regulating lipid raft-mediated EGFR activation in gastric cancer.
  • To elucidate the molecular mechanisms by which EGFR activation antagonizes TRAIL-induced apoptosis in gastric cancer cells.

Main Methods:

  • Utilized gastric cancer cell lines (SGC-7901 and MGC-803).
  • Performed knockdown of caveolin-1.
  • Employed Src kinase inhibitors.
  • Analyzed protein translocation, activation, and interactions within lipid rafts.

Main Results:

  • TRAIL induced EGFR and caveolin-1 translocation and activation within lipid rafts in gastric cancer cells.
  • Caveolin-1 knockdown partially inhibited EGFR activation and sensitized cells to TRAIL.
  • TRAIL promoted Src translocation and activation, leading to interactions with EGFR and caveolin-1.
  • Src inhibition blocked these interactions and EGFR/caveolin-1 activation, enhancing TRAIL-induced apoptosis.

Conclusions:

  • Src kinase activates EGFR via interactions with EGFR and caveolin-1 within lipid rafts.
  • This Src-mediated EGFR activation antagonizes TRAIL-induced apoptosis in gastric cancer cells.
  • Targeting this pathway may represent a therapeutic strategy for overcoming TRAIL resistance in gastric cancer.

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