Chemical Perturbation of Mcl‑1 Pre-mRNA Splicing to Induce Apoptosis in Cancer Cells

Abstract

The myeloid cell leukemia-1 (<i>MCL1</i>) 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 <i>MCL1</i> splicing with small molecule inhibitors of SF3B1 provides a means to sensitize cancer cells toward Bcl-x_L inhibitors