Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma
| Autor: | Yoshihiko Tomita, Daniel D. Billadeau, Hisashi Kawazoe, Akinori Muto, Vladimir Bilim, Sei Naito, Mototsugu Oya, Teiichi Motoyama, Kaori Yuuki, A. V. Ougolkov |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male renal cell carcinoma Cancer Research Cell Survival X-Linked Inhibitor of Apoptosis Protein Docetaxel macromolecular substances Biology urologic and male genital diseases glycogen synthase kinase-3β Glycogen Synthase Kinase 3 GSK-3 Renal cell carcinoma Pancreatic cancer medicine Humans Urea Carcinoma Renal Cell Aged Cell Proliferation Glycogen Synthase Kinase 3 beta Cell growth apoptosis NF-kappa B Cancer Middle Aged medicine.disease Kidney Neoplasms XIAP Thiazoles Proto-Oncogene Proteins c-bcl-2 Oncology Cancer cell Cancer research Female Taxoids Translational Therapeutics Kidney cancer |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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