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 Zhou, C. Articles by Boggess, J. F. Search for Related Content PubMed PubMed Citation Articles by Zhou, C. Articles by Boggess, J. F.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology [C. Z., P. A. G., J. F. B.], Department of Medicine [Y. E. W.], Lineberger Comprehensive Cancer Center [P. A. G., Y. E. W., J. F. B.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599

² To whom requests for reprints should be addressed, at Lineberger Comprehensive Cancer Center, CB#7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. Phone: (919) 966-8645; Fax: (919) 966-8212; E-mail: ywhang{at}med.unc.edu

Rapamycin exerts its biological activity by inhibiting the kinase mammalian target of rapamycin (mTOR), which regulates important cellular processes such as control of cell cycle and cell size, translation initiation, and transcription. The ability of rapamycin to inhibit cancer cell proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anticancer agents. Some investigators have hypothesized that loss of the PTEN tumor suppressor may sensitize tumor cells to the antiproliferative activity of rapamycin because PTEN loss leads to activation of the mTOR pathway. Because PTEN loss is frequent in endometrial cancer, we have characterized the effect of rapamycin in endometrial cancer cells. We show that rapamycin in the nanomolar concentration range exerts a potent growth-inhibitory effect on endometrial cancer cells through induction of cell cycle arrest. This effect is independent of PTEN status because PTEN-positive ECC-1 cells are as sensitive to rapamycin as PTEN-null Ishikawa and Hec-1B cells, suggesting that rapamycin may be effective against a broad range of endometrial cancers. We also show that rapamycin rapidly inhibits telomerase activity by decreasing the mRNA level of hTERT, the catalytic subunit of telomerase. This implies that rapamycin leads to inhibition of hTERT gene transcription. We demonstrate that rapamycin inhibits phosphorylation of downstream targets of mTOR such as p70^S6K kinase and 4E-BP1 translation repressor. This work suggests that rapamycin is a potentially useful targeted therapy for endometrial cancer and that loss of telomerase activity may be a good surrogate biomarker for assessing antitumor activity of rapamycin.

This article has been cited by other articles:

				L. Terrin, J. Dal Col, E. Rampazzo, P. Zancai, M. Pedrotti, G. Ammirabile, S. Bergamin, S. Rizzo, R. Dolcetti, and A. De Rossi Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes J. Virol., October 15, 2008; 82(20): 10175 - 10187. [Abstract] [Full Text] [PDF]

				K. H. Lu, W. Wu, B. Dave, B. M. Slomovitz, T. W. Burke, M. F. Munsell, R. R. Broaddus, and C. L. Walker Loss of Tuberous Sclerosis Complex-2 Function and Activation of Mammalian Target of Rapamycin Signaling in Endometrial Carcinoma Clin. Cancer Res., May 1, 2008; 14(9): 2543 - 2550. [Abstract] [Full Text] [PDF]

				L. Guan, K. Song, M. A. Pysz, K. J. Curry, A. A. Hizli, D. Danielpour, A. R. Black, and J. D. Black Protein Kinase C-mediated Down-regulation of Cyclin D1 Involves Activation of the Translational Repressor 4E-BP1 via a Phosphoinositide 3-Kinase/Akt-independent, Protein Phosphatase 2A-dependent Mechanism in Intestinal Epithelial Cells J. Biol. Chem., May 11, 2007; 282(19): 14213 - 14225. [Abstract] [Full Text] [PDF]