Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO₃a-dependent upregulation of death receptors

One of the major problems associated with the chemotherapy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) that selectively kills tumor cells is decreased drug resistance. This warranted the development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL. Herein, we examined the role of aldose reductase (AR) in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. We demonstrate that AR inhibition potentiates TRAIL-induced cytotoxicity in cancer cells by upregulation of both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 significantly (>85%) reduced the sensitizing effect of the AR inhibitor fidarestat on TRAIL-induced apoptosis. Further, AR inhibition also downregulates cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, and FLIP) and upregulates the expression of proapoptotic proteins such as Bax and alters mitochondrial membrane potential, leading to cytochrome c release, caspases-3 activation, and PARP cleavage. We found that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO₃a. Knockdown of FOXO₃a significantly (>80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that fidarestat potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of the AKT/FOXO₃a pathway.