TRAIL resistance in gastric cancer cells is mediated by the formation of an IGF1R/CAV1/SRC tri-complex, which can be reversed by targeting these molecules or overexpressing microRNA-194.
Identifies a potential therapeutic target for overcoming TRAIL resistance in gastric cancer; leaves open whether disrupting this.
Lipid rafts provide a biological platform for apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We previously reported that insulin-like growth factor 1 receptor (IGF1R) translocation into lipid rafts helped to explain TRAIL resistance. However, it was not clear whether TRAIL resistance was caused by the interaction of IGF1R with caveolin-1 (CAV1) and the non-receptor tyrosine kinase SRC in lipid rafts of gastric cancer cells. Here, we observed high IGF1R expression in TRAIL-resistant gastric cancer cells, and showed that IGF1R combined with both CAV1 and SRC in a native complex. TRAIL was shown to promote the formation of the IGF1R/CAV1/SRC tri-complex and the activation of these three molecules. Knockdown of IGF1R or CAV1 or inhibition of SRC activity reduced the formation of this tri-complex and enhanced TRAIL-induced apoptosis. Furthermore, the overexpression of microRNA-194 reversed TRAIL resistance by reducing IGF1R expression. In summary, TRAIL increased formation of the IGF1R/CAV1/SRC tri-complex and the activation of downstream survival pathways, leading to TRAIL resistance in gastric cancer cells.
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Guo et al. (2017) studied this question.
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