Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) selectively is able to increase apoptosis in
cancer cells as agent with minimum toxicity to noncancerous cells. However, all
cancer cells are not sensitive to TRAIL-induced apoptosis. In this study, we showed the sub-lethal concentrations of a lysosomotropic autophagy inhibitor, IITZ-01, sensitizes
cancer cells (renal, lung, and
breast carcinoma) to TRAIL-induced apoptosis through DR5 upregulation and
survivin downregulation through
ubiquitin-
proteasome pathway. Knockdown of DR5 or overexpression of
survivin inhibited combined treatment with IITZ-01 and TRAIL-induced apoptosis. IITZ-01 downregulated
protein expression of Cbl,
ubiquitin E3 ligase, and decreased expression level of Cbl markedly led to increase DR5
protein expression and TRAIL sensitivity. Moreover, IITZ-01 decreased expression level of
survivin protein via downregulation of
deubiquitinase ubiquitin-specific protease 9X (USP9X) expression. Taken together, these results provide the first evidence that IITZ-01 enhances TRAIL-mediated apoptosis through DR5 stabilization by downregulation of Cbl and USP9X-dependent
survivin ubiquitination and degradation in
renal carcinoma cells.