Platelet-activating factor activates mitogen-activated protein kinases, inhibits proliferation, induces differentiation and suppresses the malignant phenotype of human colon carcinoma cells

Abstract

Recent studies suggest that the action of plateletactivating factor (PAF), a potent phospholipid modulator of allergic and inflammatory reactions, is diverse and functions as a modulator of a variety of physiological and pathological events in many cell types and tissues. Its role (if any) in modulating the proliferation, transformation and/or differentiation of epithelial colonic cells, however, is not known. In this study, we showed that PAF is biologically active in epithelial-derived human colon carcinoma cells with different phenotypic properties. These cells expressed the PAF receptor. PAF activated three prominent mitogen-activated protein kinase modules (ERK, p38MAPK and Jun N-terminal kinases) in these cells, inhibited proliferation and induced differentiation (measured by the induction of Waf1/p21 and the induction of the differentiation-related marker CEA). The net effect of PAF treatment was the suppression of malignant cell behavior (measured by anchorage-independent growth and cellular invasion). It is concluded that PAF is a modulator of proliferation and differentiation in human epithelialderived colon carcinoma cells.

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein‐2 gene expression in enterocytes via NF‐κB activation: independence from endogenous TNF‐α and platelet‐activating factor

“…36 PAF has been found to have potent chemotactic properties on neutrophils via the production of endogenous leukotriene B4. 37 PAF is a potent activator of mitogen-activated protein kinase, 38 signal transducer and activator of transcription-3 39 and phosphoinositol-3 kinase. 40 In vivo, PAF has been shown to be produced in a model of endotoxic shock 20 and to mediate LPS-induced intestinal injury.…”

Expression of Platelet-Activating Factor Receptor: A Novel Prognosticator in Patients with Hepatocellular Carcinoma following Hepatectomy

“…PAF has been shown to be involved in allergy, inflammation, infection and endotoxic shock [3]. Various functions of PAF have also been related to tumor activities [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Melanocytic tumorigenesis was observed in PAFR transgenic mice [4], and PAF demonstrated a metastasis-promoting effect in melanoma cells [5, 6].…”

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity

“…It is the major factor responsible for endotoxin-induced diarrhoea [5,37] and necrotizing enterocolitis in the newborn [38]. PAF probably promotes inflammation via multiple mechanisms, including production and release of pro-inflammatory cytokines such as IL-8, TNFα and IL-1β [9,10,39], and activation of MAPK and NF-κB [8,40]. The increased cytokines may in turn stimulate the release of PAF [41], creating a positive feedback loop in accelerating the inflammatory response.…”

“…PAF has been recognized as an important mediator in the pathogenesis of various intestinal diseases including IBD (inflammatory bowel disease), cholera and necrotizing enterocolitis in newborns [3][4][5][6]. The effects of PAF are mediated through G-protein-coupled receptors expressed in several tissues, including the intestinal mucosa [7], leading to functional changes of numerous signalling molecules such as activation of MAPK (mitogen-activated protein kinase) and NF-κB (nuclear factor κB), induction of biosynthesis of prostaglandins, expression of PLA 2 and release of a variety of cytokines, including IL-8 (interleukin 8), IL-1β and TNFα (tumour necrosis factor α) [8][9][10][11]. Increased PAF has been reported in faeces from patients with ulcerative colitis and Crohn's disease [12].…”