CYP2S1 Modulation of Prostaglandin Synthesis in Cultured Human Lung Cells

CYP2S1 is a member of the cytochromes P450 (CYPs) superfamily:  enzymes capable of metabolizing various endogenous and exogenous compounds.  CYP2S1’s expression and metabolic profile suggests a potentially important role in carcinogenesis, particularly in lung cancer:  i) CYP2S1 is mainly expressed in the lung, ii) CYP2S1 is elevated in response to xenobiotics implicated in carcinogenesis, and iii) elevated in epithelial-derived cancers.  Recently prostaglandins derived from arachidonic acid (AA) were identified as endogenous substrates for CYP2S1.  AA is implicated in lung carcinogenesis; cyclooxygenase-2 (COX-2) is elevated in approximately 70% of lung cancers.  COX-2 catalyzes the initial step in the metabolism of AA to prostaglandin E2 (PGE2).  Elevated and reduced levels of PGE2 within lung alveolar carcinoma cells (A549) increase migration and promote apoptosis, respectively.  CYP2S1 metabolizes the PGE2 precursor prostaglandin G2 (PGG2), which may effectively divert the AA pathway, thereby regulating PGE2-mediated carcinogenesis.  We hypothesize that changes in CYP2S1 expression influences PGE2-synthesis and associated cell growth in lung cells.  To test this, we produced stable cell lines in A549 and bronchial epithelial (BEAS-2B) cells that exhibit elevated (CYP2S1-FLAG) or reduced (CYP2S1 siRNA) expression of CYP2S1, and evaluated intracellular PGE2 levels and effects on cell growth using a PGE2 ELISA and MTT assays. Reduced CYP2S1 expression in A549s stimulated a 2-fold increase in intracellular PGE2 levels and altered cell viability.  These data are consistent with an endogenous regulatory role of CYP2S1 in modulating prostaglandin synthesis in human lung cells.  This research was funded by grant # R25 GM048998-13.