Abstract
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.
Highlights
Most chemotherapeutic agents exert their cytotoxic effects in part through the induction of apoptosis
Using a platelet-activating factor (PAF)-R-negative human carcinoma cell line transduced with the PAF receptor (PAF-R) and a novel retroviral mediated antisense strategy to ablate endogenous PAF-R expression in a PAF-R-positive epithelial carcinoma cell line, we demonstrate that the PAF-R can augment apoptosis due to etoposide and mitomycin C but not other agents such as C2 ceramide and TRAIL
To test whether PAF-R-mediated activation of the nuclear factor B (NF-B) pathway was involved in the augmentation of chemotherapymediated apoptosis, we examined the ability of etoposide and mitomycin C to activate the NF-B system in KB cells as well as whether a dominant-negative inhibitor of NF-B could affect PAF-R-mediated augmentation of apoptosis in response to these chemotherapeutic agents
Summary
Most chemotherapeutic agents exert their cytotoxic effects in part through the induction of apoptosis. 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. Using a PAF-R-negative human carcinoma cell line transduced with the PAF-R and a novel retroviral mediated antisense strategy to ablate endogenous PAF-R expression in a PAF-R-positive epithelial carcinoma cell line, we demonstrate that the PAF-R can augment apoptosis due to etoposide and mitomycin C but not other agents such as C2 ceramide and TRAIL
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
