Impact of BMI1 expression on the apoptotic effect of paclitaxel in colorectal cancer

摘要

Colorectal cancer (CRC) is one of the most common cancers worldwide. Despite advances in treatment, no treatment modality specific for the different CRC phenotypes has been developed. BMI1 has been previously reported to play an important role in the regulation of cancer stem cells and cell cycle in CRC. However, the role of BMI1 in individualized treatment for CRC is largely unknown. In this study, we found that the apoptotic effect of paclitaxel is more profound in BMI1-depleted cells. The apoptotic effect is exerted by promoting caspase-8-independent apoptotic pathways after combination with paclitaxel in BMI1 knockdown cells. This effect could be totally recovered by pretreatment with caspase inhibitor compared with caspase-8 inhibitor alone. It has been reported that the levels of MCL-1 play a role in regulating cell resistance to paclitaxel treatment. Our data indicated that the downregulation of MCL-1 through the activation of GSK3beta and JNK is driven by BMI1 depletion. Consistent with in vitro data, a synergic anti-growth effect of BMI1 depletion with paclitaxel treatment was shown in vivo. In conclusion, paclitaxel has a stronger suppressive effect on tumor growth and proliferation in CRC with low BMI1 expression. Thus, in CRC patients, paclitaxel could be specifically indicated for patients with low BMI1 expression.