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

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

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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
Pages (from-to)2005-2014
Number of pages10
JournalBritish Journal of Cancer
Volume101
Issue number12
DOIs
Publication statusPublished - 2009 Dec

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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., Oya, M., Billadeau, D., Motoyama, T., & 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