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

Br J Cancer. 2009 Dec 15;101(12):2005-14. doi: 10.1038/sj.bjc.6605437. Epub 2009 Nov 17.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Renal Cell / enzymology*
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / therapy
  • Cell Proliferation
  • Cell Survival
  • Docetaxel
  • Female
  • Glycogen Synthase Kinase 3 / analysis*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Kidney Neoplasms / enzymology*
  • Kidney Neoplasms / pathology
  • Kidney Neoplasms / therapy
  • Male
  • Middle Aged
  • NF-kappa B / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Taxoids / administration & dosage
  • Thiazoles / administration & dosage
  • Urea / administration & dosage
  • Urea / analogs & derivatives
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Taxoids
  • Thiazoles
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Docetaxel
  • N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea
  • Urea
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3