This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wetterau, L. A. Articles by Cohen, P. Search for Related Content PubMed PubMed Citation Articles by Wetterau, L. A. Articles by Cohen, P.

Insulin-Like Growth Factor I Stimulates Telomerase Activity in Prostate Cancer Cells

Columbus Children’s Hospital, Ohio State University College of Medicine (L.A.W.), Columbus, Ohio 43205; Mattel Children’s Hospital, University of California (M.J.F., L.M., P.C.), Los Angeles, California 90095

Address all correspondence and requests for reprints to: Lawrence A. Wetterau, M.D., Section of Endocrinology, Columbus Children’s Hospital, Ohio State University College of Medicine, 700 Children’s Drive, Columbus, Ohio 43205-2696. E-mail: lwetterau{at}chi.osu.edu.

IGF-I has been implicated in the pathogenesis of human cancer. We sought to establish a role for IGF-I in the regulation of telomerase, an enzyme critically involved in cancer cell immortalization. Telomerase activity was assayed in LAPC-4, PC-3, and DU-145 prostate cancer cell lines treated with and without IGF-I/IGF-I analogs. Relative expression of human telomerase reverse transcriptase (hTERT) mRNA and protein was determined by quantitative RT-PCR and Western immunoblot, respectively. IGF-I stimulated baseline telomerase activity in all three cell lines, ranging from 2- to 10-fold (P < 0.05). Enhancement was noted at IGF concentrations as low as 10 ng/ml and was maximal at 100 ng/ml. Stimulation was noted by 0.5 h, was maximal by 8 h, and persisted to 48 h. A similar 3-fold enhancement (P < 0.01) was noted in response to Long-R3 IGF-I, but not in response to [Ala³¹,Leu⁶⁰]IGF-I. Pretreatment with the Akt kinase inhibitor wortmannin abolished the stimulatory IGF effect, whereas blockade of MAPK activity did not. Lastly, IGF-I provoked a 2-fold increase in hTERT mRNA and protein expression (P < 0.01). In summary, IGF-I clearly stimulates telomerase activity in prostate cancer cells through a dual mode of action, including early rapid effects probably involving phosphorylation of hTERT by Akt and later up-regulation of hTERT expression.

This work was supported in part by Grants 2R01-DK-47591 and 1RO1-AI-40203; by awards from the Department of Defense, the American Cancer Society, and the Juvenile Diabetes Foundations (to P.C.); and by National Research Scientist Award and Lawson Wilkins Pediatric Endocrine Society grants (to L.W.).

Abbreviations: A/P/S, Amphotericin/penicillin/streptomycin; FBS, fetal bovine serum; hTERT, human telomerase reverse transcriptase; hTR, human telomerase RNA; IGFBP, IGF-binding protein; IGFR, IGF receptor; PHA, phytohemagglutinin; PI3-kinase, phosphoinositol 3-kinase.

This article has been cited by other articles:

				D. L. Kleinberg, T. L. Wood, P. A. Furth, and A. V. Lee Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions Endocr. Rev., February 1, 2009; 30(1): 51 - 74. [Abstract] [Full Text] [PDF]

				L Gomez-Garcia, F M Sanchez, M T Vallejo-Cremades, I A G. de Segura, and E De Miguel del Campo Direct activation of telomerase by GH via phosphatidylinositol 3'-kinase J. Endocrinol., June 1, 2005; 185(3): 421 - 428. [Abstract] [Full Text] [PDF]

				J. Pavelic, S. Krizanac, S. Kapitanovic, L. Pavelic, M. Samarzija, F. Pavicic, S. Spaventi, M. Jakopovic, Z. Herceg-Ivanovi, and K. Pavelic The Consequences of Insulin-Like Growth Factors/Receptors Dysfunction in Lung Cancer Am. J. Respir. Cell Mol. Biol., January 1, 2005; 32(1): 65 - 71. [Abstract] [Full Text] [PDF]