Abstract
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.
Publication types
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Letter
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Research Support, N.I.H., Extramural
MeSH terms
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Alternative Splicing / drug effects*
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Apoptosis / genetics
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Biphenyl Compounds / pharmacology
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Epoxy Compounds / pharmacology*
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Morpholines / pharmacology
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Myeloid Cell Leukemia Sequence 1 Protein / genetics*
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Nitrophenols / pharmacology
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / metabolism
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Piperazines / pharmacology
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Protein Isoforms
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Pyrans / pharmacology*
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear / antagonists & inhibitors
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Ribonucleoprotein, U2 Small Nuclear / metabolism
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Sulfonamides / pharmacology
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bcl-X Protein / antagonists & inhibitors
Substances
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ABT-737
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Biphenyl Compounds
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Epoxy Compounds
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MCL1 protein, human
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Morpholines
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Phosphoproteins
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Piperazines
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Protein Isoforms
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Pyrans
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RNA Splicing Factors
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Ribonucleoprotein, U2 Small Nuclear
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SF3B1 protein, human
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Sulfonamides
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bcl-X Protein
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meayamycin
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meayamycin B