This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sourbier, C. Articles by Massfelder, T. Search for Related Content PubMed PubMed Citation Articles by Sourbier, C. Articles by Massfelder, T.

The Phosphoinositide 3-Kinase/Akt Pathway: A New Target in Human Renal Cell Carcinoma Therapy

¹ Institut National de la Sante et de la Recherche Medicale U727, Section of Renal Pharmacology and Physiopathology, University Louis Pasteur School of Medicine and Departments of ² Pathology and ³ Urology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Requests for reprints: Thierry Massfelder, Institut National de la Sante et de la Recherche Medicale U727, Section of Renal Pharmacology and Physiopathology, 11 rue Humann, Bâtiment 4, 1er étage, F67085 Strasbourg Cedex, France. Phone: 33-3-90-24-34-56; Fax: 33-3-90-24-34-59; E-mail: Thierry.Massfelder{at}medecine.u-strasbg.fr.

Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase–mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma. (Cancer Res 2006; 66(10): 5130-42)

This article has been cited by other articles:

				S. S. Singhal, J. Singhal, S. Yadav, M. Sahu, Y. C. Awasthi, and S. Awasthi RLIP76: A Target for Kidney Cancer Therapy Cancer Res., May 15, 2009; 69(10): 4244 - 4251. [Abstract] [Full Text] [PDF]

				J. Kim, E. Jonasch, A. Alexander, J. D. Short, S. Cai, S. Wen, D. Tsavachidou, P. Tamboli, B. A. Czerniak, K. A. Do, et al. Cytoplasmic Sequestration of p27 via AKT Phosphorylation in Renal Cell Carcinoma Clin. Cancer Res., January 1, 2009; 15(1): 81 - 90. [Abstract] [Full Text] [PDF]

				J. P. D. Van Huyen, L. Cheval, M. Bloch-Faure, M. F. Belair, D. Heudes, P. Bruneval, and A. Doucet GDF15 Triggers Homeostatic Proliferation of Acid-Secreting Collecting Duct Cells J. Am. Soc. Nephrol., October 1, 2008; 19(10): 1965 - 1974. [Abstract] [Full Text] [PDF]

				A. Basu, A. G. Contreras, D. Datta, E. Flynn, L. Zeng, H. T. Cohen, D. M. Briscoe, and S. Pal Overexpression of Vascular Endothelial Growth Factor and the Development of Post-Transplantation Cancer Cancer Res., July 15, 2008; 68(14): 5689 - 5698. [Abstract] [Full Text] [PDF]

				C. Sourbier, S. Danilin, V. Lindner, J. Steger, S. Rothhut, N. Meyer, D. Jacqmin, J.-J. Helwig, H. Lang, and T. Massfelder Targeting the Nuclear Factor-{kappa}B Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy Cancer Res., December 15, 2007; 67(24): 11668 - 11676. [Abstract] [Full Text] [PDF]

				L. Ying, A. B. Hofseth, D. D. Browning, M. Nagarkatti, P. S. Nagarkatti, and L. J. Hofseth Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation Cancer Res., October 1, 2007; 67(19): 9286 - 9293. [Abstract] [Full Text] [PDF]

				A. Agouni, C. Sourbier, S. Danilin, S. Rothhut, V. Lindner, D. Jacqmin, J.-J. Helwig, H. Lang, and T. Massfelder Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B Carcinogenesis, September 1, 2007; 28(9): 1893 - 1901. [Abstract] [Full Text] [PDF]