Hydroxyl radical-induced apoptosis in human tumor cells is associated with telomere shortening but not telomerase inhibition and caspase activation

Reactive oxygen species (ROS) have been found to trigger apoptosis in tumor cells. At the same time, telomerase is found to be associated with malignancy and reduced apoptosis, However little is known about the linkage between ROS such as (OH)-O-. and telomerase/telomere, To address the interrelations between (OH)-O-. and telomerase/telomere in tumor cell killing, HeLa, 293 and MW451 cells were induced to undergo apoptosis with (OH)-O-. radicals generated via Fe2+-mediated Fenton reactions (0.1 mM FeSO4 plus 0.3-0.9 mM H2O2) and telomerase activity, telomere length were measured during apoptosis, We found that during (OH)-O-.-induced apoptosis, telomere shortening took place while no changes in telomerase activity were observed. Our results suggest that (OH)-O-.-induced telomere shortening is not through telomerase inhibition but possibly a direct effect of (OH)-O-. on telomeres themselves indicating that telomere shortening but not telomerase inhibition is the primary event during (OH)-O-.-induced apoptosis, Strikingly, we also found that (OH)-O-.-induced apoptosis in HeLa cells is caspase-3-independent but is associated with reduction of mitochondrial transmembrane potential. Our results indicate that (OH)-O-. triggers apoptotic tumor cell death through a telomere-related, caspase-independent pathway. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V, All rights reserved.