Purpose: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 onTA and its regulation in cancer cells. Experimental Design:The effect of various radiation doses onTA 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 inTA 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 inTA. 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 Ca 2+ 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.

BackgroundTelomere/telomerase system has been recently recognized as an attractive target for anticancer therapy. Telomerase inhibition results in tumor regression and increased sensitivity to various cytotoxic drugs. However, it has not been fully established yet whether the mediator of these effects is telomerase inhibition per se or telomere shortening resulting from inhibition of telomerase activity. In addition, the characteristics and mechanisms of sensitization to cytotoxic drugs caused by telomerase inhibition has not been elucidated in a systematic manner.Methodology/Principal FindingsIn this study we characterized the relative importance of telomerase inhibition versus telomere shortening in cancer cells. Sensitization of cancer cells to cytotoxic drugs was achieved by telomere shortening in a length dependent manner and not by telomerase inhibition per se. In our system this sensitization was related to the mechanism of action of the cytotoxic drug. In addition, telomere shortening affected also other cancer cell functions such as migration. Telomere shortening induced DNA damage whose repair was impaired after administration of cisplatinum while doxorubicin or vincristine did not affect the DNA repair. These findings were verified also in in vivo mouse model. The putative explanation underlying the phenotype induced by telomere shortening may be related to changes in expression of various microRNAs triggered by telomere shortening.Conclusions/SignificanceTo our best knowledge this is the first study characterizing the relative impact of telomerase inhibition and telomere shortening on several aspects of cancer cell phenotype, especially related to sensitivity to cytotoxic drugs and its putative mechanisms. The microRNA changes in cancer cells upon telomere shortening are novel information. These findings may facilitate the development of telomere based approaches in treatment of cancer.

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In healthy women, plasma norepinephrine (NE) has a cycle with the highest levels occurring at ovulation and early luteal phase. We examined plasma NE cyclicity in premenstrual syndrome (PMS) patients as compared to controls, its relation to estradiol (E₂), progesterone (P), luteinizing hormone and follicle-stimulating hormone, and the correlation of these parameters with the PMS symptoms. Lack of NE cyclicity was observed in PMS patients. In controls, peak NE levels occurred at ovulation and early luteal phase. In PMS, serum E₂ was higher during the follicular phase, while P and gonadotrophins were higher especially at ovulation and the luteal phase. In the late luteal phase, E₂ levels were lower in PMS patients than in controls. A negative correlation was observed between the area under the curve for E₂ in the luteal phase and PMS somatic and mental scores. Plasma NE showed a negative correlation with abrupt mood swings, impatience, nervousness, tiredness, weakness, apathy, and headache. These data suggest that lack of NE cyclicity characterizes PMS, some symptoms being related to low E₂ levels during the late luteal phase and decreased noradrenergic activity at ovulation and the luteal phase.