Expression of PAFR as Part of a Prosurvival Response to Chemotherapy: A Novel Target for Combination Therapy in Melanoma

Abstract

Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.

Extra-virgin olive oil phenols block cell cycle progression and modulate chemotherapeutic toxicity in bladder cancer cells

“…These data are of great interest since the dose of EVOOE used for this experiment was non-toxic per se to the cells themselves, and this indicates a synergic effect in combination with paclitaxel. It can be hypothesized that the cytotoxicity enhancement of paclitaxel could be attributed to the alteration in gene expression occurring at low doses of phenolic extract, as observed in our previous study (20), that chemosensitize the cells by altering pathways involved in cell growth and proliferation such as platelet-activating factor (PAF) receptor signaling or PI3K signaling (37,41,42). …”

Anti-inflammatory effects of Perilla frutescens leaf extract on lipopolysaccharide-stimulated RAW264.7 cells

“…iNOS and the production of PGE 2 and NO in RAW264.7 cells. COX-2 and iNOS are both critical enzymes associated with macrophage-mediated development and progression of inflammation (19)(20)(21); therefore, effects of PLE on the mRNA level of COX-2 and iNOS were analyzed and quantified in LPS-stimulated RAW264.7 cells. RT-PCR analysis showed that LPS treatment alone enhances the expression of COX-2 and iNOS, and this increase was reverted by pretreatment with PLE in a dose-dependent manner (Fig.…”

Oncogenic effects of PAFR ligands produced in tumours upon chemotherapy and radiotherapy

“…The contribution of PAFRdependent signalling in tumour repopulation was also demonstrated in its response to chemo therapy and radiotherapy. PAF protects tumour cells from druginduced cell death, and the admin istration of PAFR antagonists blocks its protective effect [11][12][13] . Radiation therapy is among the most potent inducers of PAFR ligands through the oxidation of phospholipids 14 , whose forma tion is independent of LPCAT.…”