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

V. Bilim, A. Ougolkov, K. Yuuki, S. Naito, H. Kawazoe, A. Muto, M. Oya, Daniel D Billadeau, T. Motoyama, Y. Tomita

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2005-2014
Number of pages10
JournalBritish Journal of Cancer
Volume101
Issue number12
DOIs
StatePublished - Dec 2009

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Glycogen Synthase Kinase 3
Renal Cell Carcinoma
Therapeutics
Cell Survival
Kidney Neoplasms
docetaxel
Cell Proliferation
bcl-2 Genes
Survival
RNA Interference
Pancreatic Neoplasms
Leukemia

Keywords

  • Apoptosis
  • Glycogen synthase kinase-3b
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bilim, V., Ougolkov, A., Yuuki, K., Naito, S., Kawazoe, H., Muto, A., ... Tomita, Y. (2009). Glycogen synthase kinase-3: A new therapeutic target in renal cell carcinoma. British Journal of Cancer, 101(12), 2005-2014. https://doi.org/10.1038/sj.bjc.6605437

Glycogen synthase kinase-3 : A new therapeutic target in renal cell carcinoma. / Bilim, V.; Ougolkov, A.; Yuuki, K.; Naito, S.; Kawazoe, H.; Muto, A.; Oya, M.; Billadeau, Daniel D; Motoyama, T.; Tomita, Y.

In: British Journal of Cancer, Vol. 101, No. 12, 12.2009, p. 2005-2014.

Research output: Contribution to journalArticle

Bilim, V, Ougolkov, A, Yuuki, K, Naito, S, Kawazoe, H, Muto, A, Oya, M, Billadeau, DD, Motoyama, T & Tomita, Y 2009, 'Glycogen synthase kinase-3: A new therapeutic target in renal cell carcinoma', British Journal of Cancer, vol. 101, no. 12, pp. 2005-2014. https://doi.org/10.1038/sj.bjc.6605437
Bilim V, Ougolkov A, Yuuki K, Naito S, Kawazoe H, Muto A et al. Glycogen synthase kinase-3: A new therapeutic target in renal cell carcinoma. British Journal of Cancer. 2009 Dec;101(12):2005-2014. https://doi.org/10.1038/sj.bjc.6605437
Bilim, V. ; Ougolkov, A. ; Yuuki, K. ; Naito, S. ; Kawazoe, H. ; Muto, A. ; Oya, M. ; Billadeau, Daniel D ; Motoyama, T. ; Tomita, Y. / Glycogen synthase kinase-3 : A new therapeutic target in renal cell carcinoma. In: British Journal of Cancer. 2009 ; Vol. 101, No. 12. pp. 2005-2014.
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AU - Kawazoe, H.

AU - Muto, A.

AU - Oya, M.

AU - Billadeau, Daniel D

AU - Motoyama, T.

AU - Tomita, Y.

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N2 - 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.

AB - 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.

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