RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein–Independent Mechanism

The small regulator of G protein signaling protein RGS10 is a key regulator of neuroinflammation and ovarian cancer cell survival; however, the mechanism for RGS10 function in these cells is unknown and has not been linked to specific G protein pathways. RGS10 is highly enriched in microglia, and loss of RGS10 expression in microglia amplifies production of the inflammatory cytokine tumor necrosis factor α (TNF α ) and enhances microglia-induced neurotoxicity. RGS10 also regulates cell survival and chemoresistance of ovarian cancer cells. Cyclooxygenase-2 (COX-2)-mediated production of prostaglandins such as prostaglandin E 2 (PGE 2 ) is a key factor in both neuroinflammation and cancer chemoresistance, suggesting it may be involved in RGS10 function in both cell types, but a connection between RGS10 and COX-2 has not been reported. To address these questions, we completed a mechanistic study to characterize RGS10 regulation of TNF α and COX-2 and to determine if these effects are mediated through a G protein-dependent mechanism. Our data show for the first time that loss of RGS10 expression significantly elevates stimulated COX-2 expression and PGE 2 production in microglia. Furthermore, the elevated inflammatory signaling resulting from RGS10 loss was not affected by G α i inhibition, and a RGS10 mutant that is unable to bind activated G proteins was as effective as wild type in inhibiting TNF α expression. Similarly, suppression of RGS10 in ovarian cancer cells enhanced TNF α and COX-2 expression, and this effect did not require G i activity. Together, our data strongly indicate that RGS10 inhibits COX-2 expression by a G protein-independent mechanism to regulate inflammatory signaling in microglia and ovarian cancer cells.