The Gβ5 protein regulates sensitivity to TRAIL-induced cell death in colon carcinoma

Aberrant signaling via G protein-coupled receptors (GPCRs) is implicated in numerous diseases including colon cancer. The heterotrimeric G proteins transduce signals from GPCRs to various effectors. So far, the G protein subunit G beta 5 has not been studied in the context of cancer. Here we demonstrate that G beta 5 protects colon carcinoma cells from apoptosis induced by the death ligand TRAIL via different routes. The G beta 5 protein (i) causes a decrease in the cell surface expression of the TRAIL-R2 death receptor, (ii) induces the expression of the anti-apoptotic protein XIAP and (iii) activates the NF-kappa B signaling pathway. The intrinsic resistance to TRAIL-triggered apoptosis of colon cancer cells is overcome by antagonization of G beta 5. Based on these results, targeting of G proteins emerges as a novel therapeutic approach in the experimental treatment of colon cancer.