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Friday, August 04, 2006 12:23:50 AM
Inhibiting hTERT
http://www.nature.com/onc/journal/v25/n3...
Concluding remarks
It has been suspected for long that hTERT may contribute to tumorigenesis by a telomere length-independent mechanism because mutant hTERT, incapable of maintaining telomere length, can transform cell lines in vitro (Stewart et al., 2002). As shown, here, hTERT functions as an endogenous inhibitor of the mitochondrial pathway of apoptosis, in addition to its cardinal importance in tumor cell immortalization. This contention is based on the observation that downmodulation of hTERT by siRNAs has no toxic effects by itself (Figure 1), yet sensitizes cancer cells to apoptosis induction by DNA-damaging agents as well as by reactive oxygen species (Figure 2). Although suppression of hTERT sensitizes to the mitochondrial pathway of apoptosis, it has no such effect on CD95-induced cell death. The chemosensitizing effect is obtained immediately, as soon as the hTERT protein expression level is reduced (within 48–72 h). This time frame excludes the possibility that telomere erosion participates in the chemosensitizing effect.
As to the mechanisms that are involved in the sensitization to cell death induction by hTERT downmodulation, our data clearly show that p53 is not required for this effect (Figures 7 and 8). In contrast, our results point to increased activation of the Bax protein, which triggers the mitochondrial pathway of apoptosis, and Bax is required for apoptosis facilitated by hTERT inhibition (Figures 9 and 10). We did not find any effect of hTERT depletion on the expression level of Bax itself or on that of Bax-regulatory proteins such as Bak, Bcl-2, Bcl-XL, Puma/Bbc3, Noxa, Bim, Bid or Bad (not shown), suggesting that post-translational (rather than transcriptional or translational) modifications in the Bax interactome account for the enhanced activation of Bax in hTERT-depleted cells. Thus, the mechanism through which Bax is activated in this pathway remains an open question for future investigation. Santos et al. (2004) have shown that hTERT is targeted to the mitochondria and could sensitize cells to oxidative stress. Moreover, Haendeler et al. (2003, 2004) have published evidence suggesting that oxidative stress favors the nuclear export of hTERT, which in turn might contribute to the antiapoptotic activity of hTERT. Thus, a direct effect of hTERT on cytoplasmic, presumably mitochondrial, targets appears plausible, and a possible overlap between the hTERT and the Bax interactomes should be
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