Cigarette Smoke Upregulates Phospholipase A□‐Mediated Metabolic Pathway Expression in the Bladder: A Potential Promoter of Tumorigenesis

Abstract

Cigarette smoking remains the leading cause of preventable death and disease in the United States. Despite known risks, 42.1 million Americans continue to smoke, making research into tobacco‐related pathologies relevant and necessary. Tobacco smoking remains the best‐established risk factor for bladder cancer, and is implicated in primary tumor growth and metastasis. In a recently published study, we exposed bladder cancer cells to cigarette smoke extract and observed a significant increase in platelet‐activating factor (PAF) accumulation and expression of the PAF‐receptor. PAF is a downstream metabolite of phospholipase A□ (PLA□)‐catalyzed membrane phospholipid hydrolysis that results in the release of lysophospholipids and arachidonic acid. Arachidonic acid and its metabolites have been shown to be involved in inflammation and tumor progression. Immunohistological analysis of bladder cancer biopsies from smokers indicated increased PAF and PAF‐receptor expression in the tumor region when compared to normal tissue. PAF accumulation suggests an upregulation of PLA2 activity and arachidonic acid release. Accordingly, we examined the immunohistological expression of enzymes and metabolites involved in eicosanoid generation, including cyclooxygenase‐2 (COX‐2), prostaglandin E‐synthase (PGES), prostaglandin E□ (PGE□), and 15‐prostaglandin hydrogenase (15‐PGDH) in the bladder wall of mice exposed to room air and cigarette smoke. After 6 months’ exposure to cigarette smoke (48 min/day, 5 days/week), we observed increased expression of metabolic enzymes (COX‐2, PGES) involved in the production of PGE2, and a corresponding decrease in 15‐PGDH (responsible for its degradation) in the bladder wall. Immunohistological analysis of the bladder wall revealed a 2‐fold increase in expression of PGE□. This was associated with a 25% increase in COX‐2 expression and a 40% decrease in 15‐PGDH, suggesting that PGE2 accumulation is a result of increased production and decreased degradation. Our studies show for the first‐time cigarette smoke‐induced dysregulation of a PLA□‐mediated metabolic pathway which could contribute to tumorigenesis and progression. These results may provide a potential therapeutic target for cigarette smoked‐induced bladder cancer and progression.