Abstract
Breast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61-3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61-3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61-3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61-3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61-3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61-3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61-3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / genetics
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics*
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Caspases / genetics
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Cell Line
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Cell Line, Tumor
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Cyclin-Dependent Kinases / genetics
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DNA Fragmentation / drug effects
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Down-Regulation / drug effects*
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Down-Regulation / genetics
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Female
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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MCF-7 Cells
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Myeloid Cell Leukemia Sequence 1 Protein / genetics*
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Niacinamide / analogs & derivatives*
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Niacinamide / pharmacology
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Protein-Tyrosine Kinases / genetics
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Pyrimidines / pharmacology*
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Syk Kinase
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TNF-Related Apoptosis-Inducing Ligand / genetics*
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
Substances
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2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
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Intracellular Signaling Peptides and Proteins
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Pyrimidines
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Niacinamide
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Cyclin-Dependent Kinases
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Caspases
Grants and funding
New Scientist Funding in Basic Science Research Program (NRF-2014R1A1A1003831) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, Information & Communication Technology (ICT) and Future Planning (90% CONTRIBUTION RATE). Center for Women in Science, Engineering and Technology (WISET) grant funded by the Ministry of Science, ICT & Future Planning of Korea (MSIP) under the Program for Returners into R&D (KW-2015-PPD-0134), Korea (10% CONTRIBUTION RATE).