Crowe David L, Yoon Eiline
Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA.
Anticancer Res. 2003 May-Jun;23(3B):2321-8.
Regulation of apoptosis by extracellular molecules binding to cell death receptors has received much attention in recent years. Fas, a member of the tumor necrosis factor receptor superfamily, is a transmembrane protein whose extracellular domain binds its cognate ligand (FasL), which can induce apoptosis in sensitive cells. Fas ligation leads to activation of cell death proteases, thereby initiating a proteolytic cascade which results in cellular fragmentation and death. Apoptosis is also regulated by inhibitory signals which promote cell survival. The bcl2 family of proteins is composed of both inhibitors and activators of programmed cell death. The bcl2 protein itself inhibits many apoptotic stimuli while other members of the bcl2 family such as bak and bid promote cell death. Many types of cancer chemotherapy induce cellular stress leading to induction of apoptosis. Stress-activated protein kinases such as p38 have been shown to inactivate bcl2 through phosphorylation and induce cleavage of bid. Deficiency of proapoptotic bcl2 family members has been associated with drug-resistant phenotypes. We report that exposure of human squamous cell carcinoma lines to different chemotherapy drugs activates a caspase cascade which is distinct from that of receptor-mediated apoptosis. The variable sensitivity of each cancer cell line to different forms of chemotherapy was not due to differences in caspase or bcl2 family protein expression. Rather, the stress-activated protein kinase p38 was overexpressed by resistant SCC lines which correlated with reductions in proapoptotic bid and bak protein expression. These two proteins exhibit distinct patterns of intracellular localization during chemotherapy-induced apoptosis.
近年来，细胞外分子与细胞死亡受体结合对细胞凋亡的调控备受关注。Fas是肿瘤坏死因子受体超家族的成员，是一种跨膜蛋白，其细胞外结构域可结合其同源配体（FasL），后者能诱导敏感细胞发生凋亡。Fas配体结合导致细胞死亡蛋白酶激活，从而启动蛋白水解级联反应，导致细胞破碎和死亡。细胞凋亡也受促进细胞存活的抑制信号调控。bcl2蛋白家族由程序性细胞死亡的抑制剂和激活剂组成。bcl2蛋白本身可抑制多种凋亡刺激，而bcl2家族的其他成员如bak和bid则促进细胞死亡。许多类型的癌症化疗会诱导细胞应激，进而导致细胞凋亡。应激激活蛋白激酶如p38已被证明可通过磷酸化使bcl2失活，并诱导bid的裂解。促凋亡bcl2家族成员的缺陷与耐药表型有关。我们报告，将人鳞状细胞癌系暴露于不同的化疗药物会激活一种与受体介导的凋亡不同的半胱天冬酶级联反应。每个癌细胞系对不同形式化疗的敏感性差异并非由于半胱天冬酶或bcl2家族蛋白表达的差异。相反，耐药的鳞状细胞癌系中应激激活蛋白激酶p38过度表达，这与促凋亡bid和bak蛋白表达的降低相关。在化疗诱导的凋亡过程中，这两种蛋白表现出不同的细胞内定位模式。
