E3 Ubiquitin Ligase TRIP12 Controls Exit from Mitosis via Positive Regulation of MCL-1 in Response to Taxol

SIMPLE SUMMARY: Taxol is a chemotherapy drug used in treatment of multiple cancers. Taxol works by blocking an essential process of cell division called mitosis. Although, Taxol treatment shows promise in fight against cancer, many patients eventually develop resistance. Loss of function mutations in an E3 ubiquitin ligase component FBW7, are casually associated with cancer chemotherapy- and Taxol resistance. FBW7 is essential for degradation of a pro-survival protein MCL-1. In the absence of FBW7, MCL-1 protein accumulates, and cancer cells escape Taxol induced death. In this work we discover that another E3 ubiquitin ligase TRIP12 is required by cancer cells for efficient mitosis and completion of cell division. Inhibition of TRIP12 enhances Taxol induced cell death in an FBW7 and MCL-1 dependent manner. Thus, TRIP12/FBW7/MCL-1 axis is an important determinant of Taxol response in cancer cells. ABSTRACT: 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 (FBW7) mutations leads to the accumulation of its substrate MCL-1 which is associated with Taxol resistance in human cancers. We recently showed that E3 ubiquitin ligase TRIP12 is a negative regulator of FBW7 protein. In this study, we find that Taxol-induced mitotic block in cancer cells is partly controlled by TRIP12 via its positive regulation of MCL-1 protein. Genetic inhibition of TRIP12 accelerates MCL-1 protein degradation in mitosis. Notably, introducing double-point mutations in lysines 404/412 of FBW7 to arginine which makes it resistant to proteasomal degradation, leads to the sharp reduction of MCL-1 protein levels and sensitizes cancer cells to Taxol-induced cell death. Finally, TRIP12 deletion leads to enhanced mitotic arrest and cell death in an FBW7 and MCL-1 dependent manner in multiple cell lines including colorectal and ovarian cancer but not in breast cancer. Thus, the TRIP12/FBW7/MCL-1 axis may provide a therapeutic target to overcome Taxol-associated chemotherapy resistance in cancer.