Ivanov Vladimir N, Hei Tom K
Center for Radiological Research, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Exp Cell Res. 2006 May 1;312(8):1401-17. doi: 10.1016/j.yexcr.2006.01.003. Epub 2006 Feb 17.
Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-kappaB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.
大多数人类黑色素瘤在细胞表面表达Fas受体,用外源性Fas配体(FasL)处理可有效诱导这些细胞凋亡。相比之下,Fas阳性黑色素瘤中FasL的内源性表面表达受到抑制。我们在此报告使用亚砷酸钠(一种NF-κB激活抑制剂)和NS398(一种环氧合酶-2(COX-2)抑制剂)的组合来恢复表面FasL表达。我们观察到Fas阳性黑色素瘤中Fas介导的凋亡大幅增加。这是由于亚砷酸钠和NS398处理后诱导了FasL表面表达,并增加了对Fas死亡信号的敏感性。此外,通过特异性RNAi沉默COX-2表达在亚砷酸钠处理后也有效增加了表面FasL表达。表面FasL水平的上调是基于转运至细胞表面的效率增加以及FasL蛋白在细胞表面的稳定,而非FasL基因转录的加速。所获得的数据表明,亚砷酸钠与COX-2抑制剂的组合可能通过诱导FasL介导的死亡信号来影响靶癌细胞。