Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Abstract

Expression of telomerase is one of the hallmarks of tumor cells and has been used as a diagnostic biomarker and a therapeutic target in cancer. Novel findings have shown that telomerase activation in normal human epithelial cells may affect expression of several cancer-related genes, such as growth-related genes and c-myc gene, suggesting a possible role of telomerase in tumor initiation. Therefore, we hypothesized that individuals who are sensitive to mutagen challenge in terms of induced telomerase activity might have increased cancer risk. We tested this hypothesis in a bladder cancer case-control study (51 cases and 51 matched controls) by measuring baseline and ;-radiation -induced telomerase activities in peripheral blood lymphocytes. We found a significantly higher ;-radiation -induced telomerase activity in bladder cancer cases compared with the controls (1.34 versus 1.23; P = 0.044). A similar finding was also observed using the normalized telomerase activity (ratio of ;-radiation induced versus baseline; 1.49 versus 1.19; P < 0.001). In further categorizing the telomerase activity using 75% of the normalized value in the controls as a cutoff point, we found a significantly increased risk for bladder cancer associated with higher induced telomerase activity (adjusted odds ratio, 3.62; 95% confidence interval, 1.38-9.51). In quartile analysis, a dose-response association was noted between the induced telomerase activity and increased bladder cancer risk (P trend = 0.005). Our findings provide the first evidence linking the mutagen-induced telomerase activity in peripheral blood lymphocytes to the risk of bladder cancer, which warrants further investigation in large-sized studies and other cancer types. (Cancer Epidemiol Biomarkers Prev 2007;16(3):606 -9)

Ionizing Radiation Up-regulates Telomerase Activity in Cancer Cell Lines by Post-translational Mechanism via Ras/Phosphatidylinositol 3-Kinase/Akt Pathway

“…In contrast, an up-regulation of TA after irradiation was reported in peripheral blood mononuclear cells after mitogen stimulation and in hematopoietic cell lines (30). Interestingly, the group of Xing et al found that lymphocytes from normal controls did not activate telomerase after ex vivo irradiation, whereas lymphocytes isolated from patients with bladder and lung cancers exhibited telomerase activation (17). The apparent difference in response to irradiation of normal and malignant cells may reflect different signaling pathways, such as differential activation of the PI3K/Akt pathway in response to irradiation between tumor and primary endothelial cells (31).…”

“…Data regarding the effect of radiation on TA are conflicting. Several reports described upregulation, whereas others showed the opposite (12,13,17). These discrepancies in TA can be attributed to different methodologies such as different cell lines, varying doses of radiation, and different time points assessing its effect.…”

Bladder cancer SNP panel predicts susceptibility and survival

“…Telomerase activity is critical for chromosomal stability and has been associated with bladder cancer risk (Alvarez and Lokeshwar 2007; Xing et al 2007). TERT1 protein levels are a rate limiting step in telomerase activity and were associated with better survival in a previous study of 132 bladder cancer cases ( P = 0.007) (Ito et al 1998; Mavrommatis et al 2005).…”

Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

“…Inhibition of telomerase in cancer cells has been shown to impair tumor growth and sensitize cancer cells to radiation treatment, as discussed in Section 2.2.1. IR exposure was shown to up-regulate telomerase in human hematopoietic and cancer cells [183–188]. However, this is still a matter of debate, as much conflicting data exists.…”