Ionizing radiation up-regulates telomerase activity in cancer cell lines by post-translational mechanism via ras/phosphatidylinositol 3-kinase/Akt pathway.
OBJECTIVE
Telomerase is considered currently as a hallmark of cancer, and its inhibition is expected to become an important anticancer modality. In contrast to abundant data concerning the effect of cytotoxic drugs on telomerase activity (TA), there is scant information on the effect of radiation on telomerase. The mechanism of telomerase regulation by irradiation has never been evaluated in detail. In the present study, we investigated the effect of radiation on TA and its regulation in cancer cells.


METHODS
The effect of various radiation doses on TA in several malignant and nonmalignant cell lines was evaluated. All malignant cells exhibited similar telomerase response to radiation and its regulation was assessed at transcriptional and post-translational levels in K562 cells. Next step was the evaluation of the upstream signaling pathways leading to changes in TA using kinetics and specific inhibitors.


RESULTS
Radiation up-regulated TA in dose-dependent manner only in cancer cells. Telomerase was activated by phosphorylation by Akt and by cytoplasmic-nuclear shift. Transcriptional processes were not involved in TA. This telomerase regulation is mediated by Ras/phosphatidylinositol 3-kinase/Akt pathway. The canonical membrane effectors of irradiation (epidermal growth factor receptor, insulin-like growth factor-I receptor, and Ca2+ influx) were not involved in this process.


CONCLUSIONS
Radiation up-regulates telomerase activity specifically in cancer cells. This study adds to accumulating evidence pointing to post-translational level as important mode of telomerase regulation. Telomerase activation due to radiation may be detrimental in treatment of cancer. Data described in this study may add to future interventions aiming at inhibition of telomerase activation during irradiation.
Ram
Ron
R
Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Uziel
Orit
O
Eldan
Orit
O
Fenig
Eyal
E
Beery
Einat
E
Lichtenberg
Shelly
S
Nordenberg
Yardena
Y
Lahav
Meir
M
D002451:Cell Compartmentation / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D020014:K562 Cells / Q000201:enzymology; D007700:Kinetics; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism / Q000528:radiation effects*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; D018631:ras Proteins