miR-125b lowers sensitivity to apoptosis following mitotic arrest: Implications for breast cancer therapy

The process of apoptosis begins when the balance between proapoptotic and antiapoptotic stimuli is disturbed, leading to oligomerization of apoptosis effectors and disruption of the outer mitochondrial membrane. BCL-2 family proteins are the major regulators of mitochondrial pathway of apoptosis. In turn, microRNA-125b (miR-125b) is a member of microRNAs, which are short single-stranded noncoding RNAs that negatively regulate gene expression at the posttranscriptional level. miR-125b targets messenger RNAs encoding proapoptotic (BAK1, PUMA, BMF) and antiapoptotic (MCL1) BCL-2 family proteins. This mini-review briefly describes the involvement of BCL-2 family proteins in triggering apoptosis. Then, attention is paid to the differences in the activation of apoptosis with doxorubicin and paclitaxel, and finally the effect of miR-125b on paclitaxel- and doxorubicin-induced apoptosis in breast cancer cells is considered. It appears that miR-125b downregulates proteins that are significantly involved in the activation of apoptosis after paclitaxel-induced prolonged mitotic arrest or subsequent DNA damage if mitotic slippage occurs. It seems that high levels of miR-125b may not favor paclitaxel therapy, but reduction of miR-125b levels may increase paclitaxel-induced apoptosis, possibly also genotoxic-induced apoptosis, although adverse effects may also occur including decrease in doxorubicin-induced apoptosis.