The Epidermal Platelet-activating Factor Receptor Augments Chemotherapy-induced Apoptosis in Human Carcinoma Cell Lines

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 factorrelated apoptosis-inducing ligand or by C 2 ceramide. Oxidative stress and the transcription factor nuclear factor B (NF-B) are found to be involved in this augmentative effect because it was blocked by antioxidants and inhibition of the NF-B pathway using a superrepressor 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-B-dependent process.

Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

“…To our knowledge, apoptosis mediated through a GPCR-dependent activation of NF-kB was thus far only described for the platelet activating factor-receptor (PAF-R) which was shown to enhance chemotherapy-induced cell death in human carcinoma cell lines. 32 Strikingly, we also demonstrated that sst2-dependent cell sensitization to TNFa-induced apoptosis requires NF-kB activation.…”

Anti-apoptotic Actions of the Platelet-activating Factor Acetylhydrolase I α2 Catalytic Subunit

“…Previous studies have demonstrated that oxidative modification of membrane lipids during atherosclerotic injury, treatment with chemotherapeutic agents, ultraviolet B exposure, or excitoxicity is sufficient to produce PAF-like lipids (6,19,30,31,40). Our data suggest that these effects can occur in the absence of PAFR.…”

“…8C). DISCUSSION PAF-like lipids have been implicated as key apoptotic second messengers induced by a variety of pathological stressors (6,19,20,25,26,29,30,33,40). Converging evidence points to PAFR activation of the conserved mitochondrial death pathway (6, 12, 18 -20, 41).…”

“…Although the majority of PAF effects are understood to be transduced by its G-protein-coupled receptor (PAFR) (10), PAFR signaling has been shown to be both pro-and anti-apoptotic. Ectopic PAFR expression exacerbates cell death induced by etoposide and mitomycin C but protects cells from tumor necrosis factor ␣, TRAIL, and extracellular PAF (6,7,11,12). These opposing effects likely depend upon the relative ratio of NF-B-dependent pro-and anti-apoptotic gene products elicited in different cell types in response to the combination of an external apoptotic inducer and PAF (6).…”

“…Platelet-activating factor (PAF, 1 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a key mediator of neuronal death in ischemia, encephalitis, epileptic seizure, meningitis, and human immunodeficiency virus-1 dementia in vivo and participates in etoposide-, prion-, and ␤-amyloid-induced cell death in vitro (1)(2)(3)(4)(5)(6)(7). In the periphery, pathological increases in PAF concentrations underlie cytotoxicity in chronic inflammatory dermatoses and lethality in systemic anaphylaxis (8,9).…”