RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

Another possible mechanism may involve the recently described ability of chemotherapy agents such as docetaxel and doxorubicin to induce TNFα production and release from tumor cells [44] . This could, in turn, result in the activation of a specific receptor for TNFα (TNFR1) known to induce apoptosis through the activation of specific caspases [45, 46] . Consistent with this view, both TNFα and Fas ligand have been shown to induce rRNA degradation in human leukemia cells [25] . Furthermore, chemotherapy agents such as docetaxel and doxorubicin are also well known to induce reactive oxygen species (ROS) in tumor cells, which, in turn, can activate caspases and/or apoptosis [47, 48] . ROS can directly promote the phosphorylation and ubiquitination of Bcl-2 family proteins, resulting in cytochrome c release from mitochondria and caspase activation. Mitochondria appear to be both the source and target of ROS [49] [50] [51] . Indeed, Mroczek and Kufel present strong evidence that apoptosis-associated rRNA fragmentation in yeast is correlated with ROS levels, cellular response to oxidative stress, and reduced mitochondrial activity, but not caspase activity [16] . In tumor cells the mechanism could differ somewhat, considering that caspases could be activated by TNFα or ROS generation, resulting in RNA disruption. The evidence provided in the current study demonstrates that a caspase inhibitor significantly reduces docetaxel-induced RNA disruption.