Bay 61-3606 Sensitizes TRAIL-Induced Apoptosis by Downregulating Mcl-1 in Breast Cancer Cells.

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.

• Authors: So-Young Kim, Sang Eun Park, Sang-Mi Shim, Sojung Park, Kyung Kon Kim, Seong-Yun Jeong, Eun Kyung Choi, Jung Jin Hwang, Dong-Hoon Jin, Christopher Doosoon Chung, Inki Kim
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0146073 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26720004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide
• Intracellular Signaling Peptides and Proteins
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Pyrimidines
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Niacinamide
• Protein-Tyrosine Kinases
• SYK protein, human
• Syk Kinase
• Cyclin-Dependent Kinases
• Caspases

Topics

• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics)
• Caspases (genetics)
• Cell Line
• Cell Line, Tumor
• Cyclin-Dependent Kinases (genetics)
• DNA Fragmentation (drug effects)
• Down-Regulation (drug effects, genetics)
• Female
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• MCF-7 Cells
• Myeloid Cell Leukemia Sequence 1 Protein (genetics)
• Niacinamide (analogs & derivatives, pharmacology)
• Protein-Tyrosine Kinases (genetics)
• Pyrimidines (pharmacology)
• Syk Kinase
• TNF-Related Apoptosis-Inducing Ligand (genetics)
• Transcription, Genetic (drug effects, genetics)