Kim Shin, Kim Dong Eun, Kwon Taeg Kyu, Lee Jinho, Park Jong-Wook
Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea.
Department of Chemistry, Keimyung University, Daegu 42601, Republic of Korea.
Int J Oncol. 2016 Dec;49(6):2620-2628. doi: 10.3892/ijo.2016.3758. Epub 2016 Nov 3.
Previous studies have demonstrated the anticancer effects of the newly developed cyclin-dependent kinase inhibitor BAI in various cancer cells. However, the molecular mechanisms of the cellular effects induced by BAI have not been fully elucidated. The objective of this study was to investigate the mechanisms underlying the regulation of B cell lymphoma-2 (Bcl-2) family proteins in BAI-induced apoptosis of cancer cells. BAI induced poly(ADP-ribose) polymerase cleavage and DEVDase activation dose- and time-dependently. However, BAI-induced apoptosis was not involved in reactive oxygen species generation or mitogen-activated protein kinases pathways. On the other hand, BAI reduced the mitochondrial membrane potential (∆ψm) dose- and time-dependently, and induced the release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria in A549 and Caki cells. Furthermore, BAI-induced apoptosis was strongly associated with downregulation of B-cell lymphoma-extra large (Bcl-xL), but not Bcl-2, and BAI modulated the interactions among p53 and Bcl-2 family proteins in human cancer cells. Taken together, these results revealed that the regulations of Bcl-2 family proteins are correlated with BAI-induced apoptosis, suggesting that BAI is a potential multi-target agent of cancer.
先前的研究已证明新开发的细胞周期蛋白依赖性激酶抑制剂BAI在各种癌细胞中具有抗癌作用。然而，BAI诱导的细胞效应的分子机制尚未完全阐明。本研究的目的是探讨BAI诱导癌细胞凋亡过程中B细胞淋巴瘤-2（Bcl-2）家族蛋白调控的潜在机制。BAI剂量和时间依赖性地诱导聚（ADP-核糖）聚合酶裂解和DEVD酶激活。然而，BAI诱导的凋亡不涉及活性氧生成或丝裂原活化蛋白激酶途径。另一方面，BAI剂量和时间依赖性地降低线粒体膜电位（∆ψm），并在A549和Caki细胞中诱导凋亡诱导因子（AIF）和细胞色素c从线粒体释放。此外，BAI诱导的凋亡与B细胞淋巴瘤-特大（Bcl-xL）而非Bcl-2的下调密切相关，并且BAI调节人癌细胞中p53和Bcl-2家族蛋白之间的相互作用。综上所述，这些结果表明Bcl-2家族蛋白的调控与BAI诱导的凋亡相关，提示BAI是一种潜在的癌症多靶点药物。
