Phospholipase A, (PLA(2)) dependent pathways are important in the regulation of cell proliferation, differentiation, motility, and immune responses, and can be dysregulated during tumor development and progression. We show herein, for the first time, that cigarette smoking leads to an increase in platelet-activating factor (PAF) content and PAF receptor expression in human breast cancer cells and tissue. PAF production could be abrogated in triple-negative breast cancer cells by inhibition of calcium-independent PLA(2) (iPLA(2)). We also demonstrate that cigarette smoke induces the expression of cycLooxygenase-2 and microsomal prostaglandin E synthase-1 and reduces 15-hydroxyprostaglandin dehydrogenase, resulting in prostaglandin E-2 release in human breast cancer. Increased cyclooxygenase-2 expression and prostaglandin E-2 release could be abrogated in metastatic breast cancer cells by inhibition of iPLA(2). These studies indicate that iPLA(2)-dependent metabolic pathways play an important role in tumor initiation or progression in smokers, representing novel therapeutic targets for breast cancer patients who smoke.
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