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.
So-Young Kim  1 ,  Sang Eun Park  1 ,  Sang-Mi Shim  2 ,  Sojung Park  1 ,  Kyung Kon Kim  1  3 ,  Seong-Yun Jeong  1  3  4 ,  Eun Kyung Choi  5  4 ,  Jung Jin Hwang  1  3  4 ,  Dong-Hoon Jin  3  4 ,  Christopher Doosoon Chung  1 ,  Inki Kim  1  3
Affiliations
  • 1. ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
  • 2. Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea.
  • 3. Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • 4. Institute for Innovative Cancer Research, ASAN Medical Center, Seoul, Republic of Korea.
  • 5. Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
PMID: 26720004 DOI: 10.1371/journal.pone.0146073
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.

Products