Abstract
1835
Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the telomerase holoenzyme, required for telomerase maintenance and often re-activated in human cancers. By dint of these activities, hTERT has been widely used for cellular immortalization. However recent advances in the telomerase field suggest new functions for hTERT in conferring increased resistance against apoptosis inducing agents and DNA damaging drugs. In an effort to unravel the biological activity of this remarkable protein, we are investigating the cross talk between hTERT and cellular redox status during the process of carcinogenesis. To that end, our work over the years has highlighted the death inhibitory and/or tumor promoting activity of a slight pro-oxidant state, invariably associated with the neoplastic phenotype. For example, we linked the death inhibitory activity of Bcl-2 to its ability to create a slight pro-oxidant state in tumor cells. In addition, recent evidence has linked an increase in Bcl-2 expression to increased telomerase activity. Intrigued by these findings, we are interested in asking if tumor cell redox status could affect hTERT expression and activity and vice versa. To do so, we stably overexpressed hTERT in HeLa cells, and demonstrate that hTERT overexpression affects intracellular ROS status. We hypothesize that alteration(s) in intracellular redox status upon overexpression of hTERT may modify tumor cell response to apoptotic death triggers. In this regard, we provide evidence that hTERT may play a crucial role in regulating mitochondria mediated cell death pathway. These data provide a novel biological activity of hTERT, which could have implications for designing effective therapeutic strategies against cancer cells. The molecular mechanisms of altered ROS balance by hTERT and interaction of hTERT with pro-apoptotic proteins and their effect on cell fate is currently the focus of our studies.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA
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