title: 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 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.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.forename: Michael D
authors.initials: MD
authors.lastname: Southall
authors.forename: Qiaofang
authors.initials: Q
authors.lastname: Yi
authors.forename: Yong
authors.initials: Y
authors.lastname: Pei
authors.forename: Davina
authors.initials: D
authors.lastname: Lewis
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Hassani
authors.forename: Dan
authors.initials: D
authors.lastname: Spandau
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor