Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3 β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF- κB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3 β and to assess the anti-cancer effect of GSK-3 β inhibition in RCC.
Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3 β in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT–PCR, BrDU incorporation and MTS assays to study the effect of GSK-3 β inactivation on renal cancer cell proliferation and survival.
We detected aberrant nuclear accumulation of GSK-3 β in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF- κB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells.