Insulin-like growth factor I stimulates telomerase activity in prostate cancer cells.
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 [Ala(31),Leu(60)]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.
Wetterau
Lawrence A
LA
Columbus Children's Hospital, Ohio State University College of Medicine, Columbus, Ohio 43205, USA. lwetterau@chi.osu.edu
Francis
Malik J
MJ
Ma
Liqun
L
Cohen
Pinchas
P
D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D004268:DNA-Binding Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D019098:Telomerase; C494918:AKT1 protein, human