TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells.

Abstract

Most gastric cancer cells are resistant to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Since TRAIL resistance is associated with lipid rafts, in which both death receptors and epidermal growth factor receptors (EGFR) are enriched, our aim is to identify how lipid raft-regulated receptor redistribution influences the sensitivity of TRAIL in gastric cancer cells. In TRAIL-resistant gastric cancer cells, TRAIL did not induce effective death-inducing signalling complex (DISC) formation in lipid rafts, accompanied with EGFR translocation into lipid rafts, and activation of EGFR pathway. Knockdown of casitas B-lineage lymphoma-b (Cbl-b) enhanced TRAIL-induced apoptosis by promoting DISC formation in lipid rafts. However, knockdown of Cbl-b also enhanced EGFR translocation into lipid rafts and EGFR pathway activation induced by TRAIL. Either using inhibitors of EGFR or depletion of EGFR with small interfering RNA (siRNA) prevented EGFR pathway activation, and thus increased TRAIL-induced apoptosis, especially in Cbl-b knockdown clones. Taken together, TRAIL-induced EGFR activation through Cbl-b-regulated EGFR redistribution in lipid rafts antagonised TRAIL-induced apoptosis. The contribution of DISC formation and the inhibition of EGFR signal triggered in lipid rafts are both essential for increasing the sensitivity of gastric cancer cells to TRAIL.

• Authors: Ling Xu, Ye Zhang, Jing Liu, Jinglei Qu, Xuejun Hu, Fan Zhang, Huachuan Zheng, Xiujuan Qu, Yunpeng Liu
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 48 Issue 17 Pg. 3288-99 (Nov 2012) ISSN: 1879-0852 [Electronic] England
• PMID: 22456178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Death Domain Receptor Signaling Adaptor Proteins
• TNF-Related Apoptosis-Inducing Ligand
• CBLB protein, human
• Proto-Oncogene Proteins c-cbl
• ErbB Receptors

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Death Domain Receptor Signaling Adaptor Proteins (physiology)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Membrane Microdomains (metabolism)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-cbl (physiology)
• Stomach Neoplasms (drug therapy, pathology)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)