title: 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.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sang-Mi
authors.initials: SM
authors.lastname: Shim
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Park
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyung Kon
authors.initials: KK
authors.lastname: Kim
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.|Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
authors.forename: Christopher Doosoon
authors.initials: CD
authors.lastname: Chung
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.|Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Inki
authors.initials: I
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D020169:Caspases / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D061986:MCF-7 Cells; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D000072377:Syk Kinase; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
chemical_list: C477642:2-(7-(3,4-dimethoxyphenyl)imidazo(1,2-c)pyrimidin-5-ylamino)nicotinamide; D047908:Intracellular Signaling Peptides and Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D009536:Niacinamide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D018844:Cyclin-Dependent Kinases; D020169:Caspases