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Implications For Platelet Activating Factor Receptor Antagonism For Managing Bladder Cancer Progression
Author(s) -
McHowat Jane,
Marentette John
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.697.6
Subject(s) - platelet activating factor , bladder cancer , inflammation , cancer cell , metastasis , cancer , cancer research , receptor , chemistry , phospholipase a2 , arachidonic acid , eicosanoid , platelet activating factor receptor , endocrinology , medicine , biochemistry , enzyme , antagonist
Cigarette smoking is the number one risk factor for bladder cancer development and epidemiological data suggests that nearly half of all bladder cancer patients have a history of smoking. In addition to stimulating growth of a primary tumor, it has been shown that there is a correlation between smoking and tumor metastasis. Platelet activating factor (PAF) is an inflammatory cell recruiter that is expressed on the endothelium during times of inflammation and through binding with the PAF‐receptor (PAFR) facilitates transendothelial migration of circulating inflammatory cells. PAF has been implicated in primary tumor growth and interactions with the PAFR have been shown to stimulate cellular growth. PAF is generated through hydrolysis of membrane phospholipids by the activity of calcium‐independent phospholipase A 2 (iPLA 2 ) which removes the sn‐ ‐2 fatty acid yielding a free fatty acid, arachidonic acid, and a lysophospholipid. Acetylation of the newly formed lysophospholipid results in PAF production. Under normal circumstances, PAF is maintained at a low concentration by PAF‐acetylhydrolase (PAF‐AH) resulting in the inactive lyso‐PAF. In the present study, we show that cigarette smoke extract (CSE) exposure of bladder cancer cells inhibits PAF‐AH activity and increases iPLA‐ 2 activity resulting in increased PAF accumulation. In addition to PAF accumulation, CSE increases PAFR expression. Furthermore, by immunohistochemical analysis of tumor biopsy samples from bladder cancer patients we detected increased PAF, iPLA 2 and the PAFR in tumor regions when compared to surrounding tissue. This data highlights a pathway that is upregulated in tumor areas of bladder cancer patients and that is influenced by CSE which could facilitate primary tumor growth and increase metastatic potential. Targeting of the PAF‐PAFR interaction could serve as a beneficial therapeutic target for managing further growth of a developing tumor.