Rudner Justine, Elsaesser Simon Johannes, Müller Arndt-Christian, Belka Claus, Jendrossek Verena
University of Tübingen, Department of Radiation Oncology, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
Biochem Pharmacol. 2010 Jan 1;79(1):10-20. doi: 10.1016/j.bcp.2009.07.021. Epub 2009 Aug 7.
The cyclooxygenase-2 inhibitor Celecoxib is a potent inducer of apoptosis in tumor cells. In most cellular systems Celecoxib induces apoptosis via an intrinsic, mitochondrial apoptosis pathway. We recently showed that in Bax-negative Jurkat cells expression of pro-apoptotic Bak is essential for Celecoxib-induced mitochondrial damage and apoptosis induction. Aim of the present study was to identify specific pro- and anti-apoptotic members of the Bcl-2 family involved in the regulation of Bak activation, and subsequent apoptosis upon treatment with Celecoxib in the Jurkat cell model. Our results show that apoptosis in response to Celecoxib required the presence of Noxa and downregulation of the anti-apoptotic protein Mcl-1. Celecoxib-induced Bak activation and subsequent apoptosis could be inhibited by overexpression of Bcl-xL but not by the very similar Bcl-2. In Bcl-xL-overexpressing cells neutralization of both, Mcl-1 and Bcl-xL, was prerequisite for an efficient induction of apoptosis. Our data reveal an important role of the Mcl-1/Noxa axis for Celecoxib-induced apoptosis and suggest that Celecoxib may be of value for treatment of tumors addicted to Mcl-1 and for combined treatment approaches targeting anti-apoptotic Bcl-2 family members.
环氧化酶-2抑制剂塞来昔布是肿瘤细胞凋亡的有效诱导剂。在大多数细胞系统中，塞来昔布通过内在的线粒体凋亡途径诱导凋亡。我们最近发现，在Bax阴性的Jurkat细胞中，促凋亡蛋白Bak的表达对于塞来昔布诱导的线粒体损伤和凋亡诱导至关重要。本研究的目的是确定参与调节Bak激活以及随后在Jurkat细胞模型中用塞来昔布处理后凋亡的Bcl-2家族的特定促凋亡和抗凋亡成员。我们的结果表明，对塞来昔布的凋亡反应需要Noxa的存在和抗凋亡蛋白Mcl-1的下调。塞来昔布诱导的Bak激活和随后的凋亡可被Bcl-xL的过表达抑制，但不能被非常相似的Bcl-2抑制。在过表达Bcl-xL的细胞中，中和Mcl-1和Bcl-xL两者是有效诱导凋亡的先决条件。我们的数据揭示了Mcl-1/Noxa轴在塞来昔布诱导的凋亡中的重要作用，并表明塞来昔布可能对治疗依赖Mcl-1的肿瘤以及针对抗凋亡Bcl-2家族成员的联合治疗方法有价值。
