期刊
ACS CHEMICAL BIOLOGY
卷 8, 期 5, 页码 895-900出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb300602j
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资金
- US National Cancer Institute [R01 CA120792, 3P50 CA097190 0751]
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.
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