rRNA disruption: a predictive marker of response to taxane chemotherapy

Abstract

A recent clinical trial for locally advanced breast cancer patients treated with epirubicin and docetaxel prior to surgery reported significant dose-dependent reductions in tumour RNA integrity values which correlated with pathological complete response. The purpose of the present study was to assess whether similar chemotherapy-dependent alterations in RNA integrity could occur in vitro and to assess its relationship, if any, to apoptosis. Treatment of wildtype A2780 ovarian carcinoma cells with taxanes resulted in dose- and time-dependent RNA degradation, identified as several unique bands on electropherograms having mobilities lower than the 28S and 18S rRNAs. We refer to this chemotherapy-dependent generation of aberrant RNA bands on electropherograms as “RNA disruption”. RNA disruption was found to be temporally associated with the induction of apoptosis, as determined by the appearance of a sub G1 peak of DNA content, positive annexin-V staining, and both PARP-1 and caspase-3 cleavage. Treatment of cells with a caspase-3 inhibitor resulted in a significant reduction in rRNA disruption, suggesting the involvement of caspase-3 or related caspases in RNA disruption. In contrast, docetaxel-dependent rRNA disruption was absent when docetaxel was administered to docetaxel-resistant A2780DXL cells, indicating that changes in RNA integrity may possibly differentiate between responsive and non-responsive tumours in cancer patients.