Glycogen synthase kinase-3: A new therapeutic target in renal cell carcinoma

Abstract

Background: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3Β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-B)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3Β and to assess the anti-cancer effect of GSK-3Β inhibition in RCC. Methods: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3Β 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-3Β inactivation on renal cancer cell proliferation and survival. Results: We detected aberrant nuclear accumulation of GSK-3Β 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-B 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. Conclusions: Our results show nuclear accumulation of GSK-3Β as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer. © 2009 Cancer Research UK.