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 Gβ5 has not been studied in the context of cancer. Here we demonstrate that Gβ5 protects colon carcinoma cells from apoptosis induced by the death ligand TRAIL via different routes. The Gβ5 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-κB signaling pathway. The intrinsic resistance to TRAIL-triggered apoptosis of colon cancer cells is overcome by antagonization of Gβ5. Based on these results, targeting of G proteins emerges as a novel therapeutic approach in the experimental treatment of colon cancer.