[HTML][HTML] Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma
V Bilim, A Ougolkov, K Yuuki, S Naito… - British journal of …, 2009 - nature.com
V Bilim, A Ougolkov, K Yuuki, S Naito, H Kawazoe, A Muto, M Oya, D Billadeau, T Motoyama…
British journal of cancer, 2009•nature.comBackground: 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-κB)-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 …
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-κB)-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 …
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-κB)-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-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.
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.
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