Lee Yoon-Jin, Lee Yong-Jin, Lee Sang-Han
Soonchunhyung Environmental Health Center for Asbestos; Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Cheonan 330-090, Korea.
Soonchunhyung Environmental Health Center for Asbestos, College of Medicine, Soonchunhyang University, Cheonan 330-090, Korea.
BMB Rep. 2015 Mar;48(3):166-71. doi: 10.5483/bmbrep.2015.48.3.105.
We previously demonstrated that resveratrol and clofarabine elicited a marked cytotoxicity on malignant mesothelioma (MM) MSTO-211H cells but not on the corresponding normal mesothelial MeT-5A cells. Little is known of the possible molecules that could be used to predict preferential chemosensitivity on MSTO-211H cells. Resveratrol and clofarabine induced down-regulation of Mcl-1 protein level in MSTO-211H cells. Treatment of cells with cycloheximide in the presence of proteasome inhibitor MG132 suggested that Mcl-1 protein levels were regulated at the post-translational step. The siRNA-based knockdown of Mcl-1 in MSTO-211H cells triggered more growth-inhibiting and apoptosis-inducing effects with the resultant cleavages of procaspase-3 and its substrate PARP, increased caspase-3/7 activity, and increased percentage of apoptotic propensities. However, the majority of the observed changes were not shown in MeT-5A cells. Collectively, these studies indicate that the preferential activation of caspase cascade in malignant cells might have important applications as a therapeutic target for MM.
我们先前证明，白藜芦醇和氯法拉滨对恶性间皮瘤（MM）MSTO-211H细胞具有显著的细胞毒性，但对相应的正常间皮细胞MeT-5A细胞则无此作用。对于可用于预测对MSTO-211H细胞的优先化学敏感性的潜在分子，人们了解甚少。白藜芦醇和氯法拉滨可诱导MSTO-211H细胞中Mcl-1蛋白水平下调。在蛋白酶体抑制剂MG132存在的情况下，用环己酰亚胺处理细胞表明，Mcl-1蛋白水平在翻译后步骤受到调节。基于小干扰RNA（siRNA）敲低MSTO-211H细胞中的Mcl-1，会引发更多的生长抑制和凋亡诱导作用，导致前半胱天冬酶-3及其底物聚（ADP-核糖）聚合酶（PARP）裂解、半胱天冬酶-3/7活性增加以及凋亡倾向百分比升高。然而，在MeT-5A细胞中未观察到大多数这些变化。总体而言，这些研究表明，恶性细胞中半胱天冬酶级联反应的优先激活作为MM的治疗靶点可能具有重要应用。
