Chemical perturbation of Mcl-1 pre-mRNA splicing to induce apoptosis in cancer cells

The myeloid cell leukemia-1 (MCL1) gene encodes antiapoptotic Mcl-1(L) and proapoptotic Mcl-1(S) proteins. In Cancer, the Mcl-1(L)/Mcl-1(S) ratio is very high, accounting for the antiapoptotic nature of Cancer cells. As such, reducing this ratio can render the Cancer cells prone to Apoptosis. The Mcl-1(L)/Mcl-1(S) ratio is determined in the alternative pre-mRNA splicing step that is regulated by splicing factor 3B1 (SF3B1). Here, we report that meayamycin B, a potent inhibitor of SF3B1, reversed the dominant isoform from Mcl-1(L) to Mcl-1(S) at the mRNA and protein levels. The resulting proapoptotic cellular environment was further exploited; when meayamycin B was combined with Bcl-x(L) inhibitor ABT-737, the combination treatment triggered Apoptosis in nonsmall cell lung Cancer A549 and H1299 cells that were otherwise resistant to ABT-737. These results demonstrate that perturbation of the MCL1 splicing with small molecule inhibitors of SF3B1 provides a means to sensitize Cancer cells toward Bcl-x(L) inhibitors.