Lipid raft-regulated IGF-1R activation antagonizes TRAIL-induced apoptosis in gastric cancer cells

FEBS Lett. 2013 Nov 29;587(23):3815-23. doi: 10.1016/j.febslet.2013.10.007. Epub 2013 Oct 22.

Abstract

Gastric cancer cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the resistance mechanism is not fully understood. In human gastric cancer MGC803 and BGC823 cells, TRAIL induces insulin-like growth factor-1 receptor (IGF-1R) pathway activation. Treatment with IGF-1R inhibitor OSI-906 or small interfering RNAs against IGF-1R, prevents IGF-1R pathway activation and increases TRAIL-induced apoptosis. The TRAIL-induced IGF-1R pathway activation is promoted by IGF-1R translocation into lipid rafts. Moreover, the translocation of IGF-1R into lipid rafts is regulated by Casitas B-lineage lymphoma b (Cbl-b). Taken together, TRAIL-induced IGF-1R activation antagonizes TRAIL-induced apoptosis by Cbl-b-regulated distribution of IGF-1R in lipid rafts.

Keywords: Cbl-b; IGF-1R; Lipid raft; TRAIL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis*
  • Cell Line, Tumor
  • Humans
  • Imidazoles / pharmacology
  • Membrane Microdomains / metabolism*
  • Protein Transport
  • Proto-Oncogene Proteins c-cbl / metabolism
  • Pyrazines / pharmacology
  • RNA, Small Interfering
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction / drug effects
  • Stomach Neoplasms / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*

Substances

  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • Adaptor Proteins, Signal Transducing
  • Imidazoles
  • Pyrazines
  • RNA, Small Interfering
  • TNF-Related Apoptosis-Inducing Ligand
  • CBLB protein, human
  • Proto-Oncogene Proteins c-cbl
  • Receptor, IGF Type 1