Trametinib potentiates TRAIL-induced apoptosis via FBW7-dependent Mcl-1 degradation in colorectal cancer cells.

: Trametinib is a MEK1/2 inhibitor and exerts anticancer activity against a variety of cancers. However, the effect of Trametinib on colorectal cancer (CRC) is not well understood. In the current study, our results demonstrate the ability of sub-toxic doses of Trametinib to enhance TRAIL-mediated apoptosis in CRC cells. Our findings also indicate that Trametinib and TRAIL activate caspase-dependent apoptosis in CRC cells. Moreover, Mcl-1 overexpression can reduce apoptosis in CRC cells treated with Trametinib with or without TRAIL. We further demonstrate that Trametinib degrades Mcl-1 through the proteasome pathway. In addition, GSK-3β phosphorylates Mcl-1 at S159 and promotes Mcl-1 degradation. The E3 ligase FBW7, known to polyubiquitinate Mcl-1, is involved in Trametinib-induced Mcl-1 degradation. Taken together, these results provide the first evidence that Trametinib enhances TRAIL-mediated apoptosis through FBW7-dependent Mcl-1 ubiquitination and degradation.