Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma.
BACKGROUND
Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3beta positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kappaB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3beta and to assess the anti-cancer effect of GSK-3beta inhibition in RCC.


METHODS
Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3beta 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-3beta inactivation on renal cancer cell proliferation and survival.


RESULTS
We detected aberrant nuclear accumulation of GSK-3beta 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-kappaB 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-3beta 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.
Bilim
V
V
Department of Urology, Yamagata University School of Medicine, Iida-nishi 2-2-2, Yamagata 990-9585, Japan.
Ougolkov
A
A
Yuuki
K
K
Naito
S
S
Kawazoe
H
H
Muto
A
A
Oya
M
M
Billadeau
D
D
Motoyama
T
T
Tomita
Y
Y
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D049109:Cell Proliferation; D002470:Cell Survival; D000077143:Docetaxel; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D013844:Thiazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000077143:Docetaxel; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3