The epidermal platelet-activating factor receptor augments chemotherapy-induced apoptosis in human carcinoma cell lines
The epidermal platelet-activating factor receptor augments chemotherapy-induced apoptosis in human carcinoma cell lines
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DOI：
10.1074/jbc.m211287200
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发表时间：
2003-05-09
影响因子：
4.8
通讯作者：
Travers, JB
中科院分区：
文献类型：
--
作者：
Li, T;Southall, MD;Travers, JB
大多数化疗药物部分通过诱导细胞凋亡发挥其细胞毒性作用。此外，许多化疗药物是强效的促氧化应激因子。虽然脂质介质血小板活化因子（PAF）是在氧化应激下合成的，而且许多表皮癌都表达PAF受体，但PAF是否参与化疗药物诱导的细胞凋亡尚不清楚。这些研究利用逆转录病毒介导的人PAF受体阴性的人表皮癌细胞KB与人PAF受体（PAF- r）的转导，以及用逆转录病毒介导的诱导反义PAF- r载体消融癌细胞HaCaT中的内源性PAF- r，建立了模型系统，研究了PAF系统在化疗介导的细胞毒性中的作用。在这些模型中，PAF-R的存在导致化疗药物依托泊苷和丝裂霉素C诱导的细胞凋亡增加，但不受肿瘤坏死因子相关的细胞凋亡诱导配体或C-2神经酰胺的影响。氧化应激和转录因子核因子kappaB （NF-kappaB）被发现参与了这种增强作用，因为它被抗氧化剂和NF-kappaB途径的抑制所阻断，这些研究为表皮PAF-R通过NF-kappaB依赖性过程增强化疗诱导的凋亡效应提供了新的途径。
Most chemotherapeutic agents exert their cytotoxic effects in part through the induction of apoptosis. In addition, many chemotherapeutic agents are potent pro-oxidative stressors. Although the lipid mediator platelet-activating factor (PAF) is synthesized in response to oxidative stress, and many epidermal carcinomas express PAF receptors, it is not known whether PAF is involved in chemotherapeutic agent-induced apoptosis. These studies examined the role of the PAF system in chemotherapy-mediated cytotoxicity using model systems created by retroviral mediated transduction of the PAF receptor-negative human epidermal carcinoma cell line KB with the human PAF receptor (PAF-R) and ablation of the endogenous PAF-R in the carcinoma cell line HaCaT with a retroviral mediated inducible antisense PAF-R vector. The presence of the PAF-R in these models resulted in an augmentation of apoptosis induced by chemotherapeutic agents etoposide and mitomycin C but not by tumor necrosis factor-related apoptosis-inducing ligand or by C-2 ceramide. Oxidative stress and the transcription factor nuclear factor kappaB (NF-kappaB) are found to be involved in this augmentative effect because it was blocked by antioxidants and inhibition of the NF-kappaB pathway using a super-repressor form of inhibitor B. These studies provide evidence for a novel pathway whereby the epidermal PAF-R can augment chemotherapy-induced apoptotic effects through an NF-kappaB-dependent process.