Crowe D L, Boardman M L, Fong K S
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles 90033, USA.
Anticancer Res. 1998 Sep-Oct;18(5A):3163-70.
Deregulation of cell death pathways is an important feature of tumorigenesis. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein that can transduce cell death signals via a proteolytic cascade upon crosslinking or ligand binding. Fas has been implicated in the cell turnover of normal stratified squamous epithelia. To determine if altered Fas mediated cell death pathways participate in epithelial tumorigenesis, we examined squamous cell carcinoma (SCC) lines for sensitivity to Fas ligand (FasL) or an agonistic anti-Fas antibody. All cell lines examined were resistant to FasL mediated cell death. The carcinoma cell line SCC71 was also highly resistant to anti-Fas antibody. Another line, SCC9, underwent rapid cell death with characteristic features of apoptosis after exposure to anti-Fas antibody. However, binding of both FasL and anti-Fas antibody recruited downstream effector molecules to the Fas cytoplasmic domain in both SCC9 and SCC71 cells. Inhibition of the caspase 3- but not the ICE family of cell death proteases blocked apoptosis in SCC9 cells independently of expression of the anti-apoptotic protein bcl2. We concluded that Fas differentially mediates apoptosis in SCC lines by activation of caspase 3 family members but independent of bcl2 expression.
细胞死亡途径的失调是肿瘤发生的一个重要特征。Fas是肿瘤坏死因子受体超家族的成员，是一种跨膜蛋白，在交联或配体结合后可通过蛋白水解级联反应转导细胞死亡信号。Fas与正常复层鳞状上皮的细胞更新有关。为了确定Fas介导的细胞死亡途径改变是否参与上皮肿瘤发生，我们检测了鳞状细胞癌（SCC）细胞系对Fas配体（FasL）或抗Fas激动性抗体的敏感性。所有检测的细胞系均对FasL介导的细胞死亡具有抗性。癌细胞系SCC71对抗Fas抗体也具有高度抗性。另一个细胞系SCC9在暴露于抗Fas抗体后经历了具有凋亡特征的快速细胞死亡。然而，FasL和抗Fas抗体的结合在SCC9和SCC71细胞中均将下游效应分子募集到Fas胞质结构域。抑制半胱天冬酶3而非ICE家族的细胞死亡蛋白酶可独立于抗凋亡蛋白bcl2的表达阻断SCC9细胞中的凋亡。我们得出结论，Fas通过激活半胱天冬酶3家族成员但独立于bcl2表达，在SCC细胞系中差异性地介导凋亡。
