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

PLoS One. 2015 Dec 31;10(12):e0146073. doi: 10.1371/journal.pone.0146073. eCollection 2015.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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

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).