Kim So-Young, Park Sang Eun, Shim Sang-Mi, Park Sojung, Kim Kyung Kon, Jeong Seong-Yun, Choi Eun Kyung, Hwang Jung Jin, Jin Dong-Hoon, Chung Christopher Doosoon, Kim Inki
ASAN Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea.
Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea.
PLoS One. 2015 Dec 31;10(12):e0146073. doi: 10.1371/journal.pone.0146073. eCollection 2015.
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.
乳腺癌细胞通常会对肿瘤坏死因子相关凋亡诱导配体（TRAIL）产生耐药性，因此需要敏化剂的辅助。在我们的研究中，我们已经证明脾酪氨酸激酶（Syk）抑制剂Bay 61 - 3606被鉴定为一种TRAIL敏化剂。Bay 61 - 3606增强TRAIL诱导的细胞凋亡伴随着Bak、半胱天冬酶的强烈激活以及DNA片段化。在作用机制方面，Bay 61 - 3606通过两种调节髓系细胞白血病序列-1（Mcl - 1）的机制使细胞对TRAIL敏感。首先，Bay 61 - 3606通过调节Mcl - 1磷酸化触发Mcl - 1的泛素依赖性降解。其次，Bay 61 - 3606在转录水平下调Mcl - 1表达。在这种情况下，Bay 61 - 3606作为细胞周期蛋白依赖性激酶（CDK）9的抑制剂而非Syk发挥作用。总之，Bay 61 - 3606下调乳腺癌细胞中Mcl - 1的表达并使癌细胞对TRAIL介导的凋亡敏感。
