| Summary: | Chemotherapy resistance is a major hurdle in cancer treatment. Taxol-based chemotherapy is widely used in the treatment of cancers including breast, ovarian, and pancreatic cancer. Loss of function of the tumor suppressor F-box WD-40 domain containing 7 (<i>FBW7</i>) mutations leads to the accumulation of its substrate <i>MCL-1</i> which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase <i>TRIP12</i> is a negative regulator of <i>FBW7</i> protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by <i>TRIP12</i> via its positive regulation of <i>MCL-1</i> protein. Genetic inhibition of <i>TRIP12</i> accelerates <i>MCL-1</i> protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of <i>FBW7</i> to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of <i>MCL-1</i> protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, <i>TRIP12</i> deletion leads to enhanced mitotic arrest and cell death in an <i>FBW7</i> and <i>MCL-1</i> dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the <i>TRIP12</i>/<i>FBW7</i>/<i>MCL-1</i> axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.
|
|---|