Regulator of G protein Signaling 10 (RGS10) suppresses COX-2 and TNFα in microglia and cancer cells through a G protein-independent mechanism

[Speaker] Shelley Hooks:1
[Co-author] Mohammed Alqinyah:1, Faris Almutairi:1, Menbere Wendimu:1
1:University of Georgia, USA

Regulators of G-protein signaling (RGS) proteins classically act negative regulators of heterotrimeric G-proteins to terminate signaling initiated by G-protein coupled receptors. As such, RGS proteins play critical roles in the physiology and pathology of diverse systems. However, an increasing number of studies report RGS protein activities that are independent of G-protein regulation. The small RGS protein RGS10 regulates inflammatory and survival signaling in multiple cell types, and has been proposed as a potential drug target in neuroinflammatory disease and ovarian cancer. RGS10 is highly enriched in immune cells, including microglia, peripheral macrophages, and osteoclasts. Loss of RGS10 expression in microglia amplifies production of the inflammatory cytokines TNFα and enhances microglia-induced neurotoxicity, but the mechanism for RGS10 effects is unknown. Similarly, RGS10 regulates cell survival and chemoresistance of ovarian cancer cells through an unknown mechanism. Cyclooxygenase-2 (COX-2) mediated production of prostaglandins such as PGE2 is a key factor in both inflammation 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 TNFα 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 lipopolysaccharide-stimulated COX-2 expression and release of PGE2 from microglia. Furthermore, the elevated inflammatory signaling resulting from RGS10 loss was not affected by Gαi inhibition, and a RGS10 mutant that is unable to bind activated G-proteins was as effective in inhibiting TNFα expression as wild type RGS10. We also show for the first time that RGS10 regulates TNFα and COX-2 inflammatory signaling in ovarian cancer cells through a G-protein independent mechanism. Together, our data strongly indicate that RGS10 inhibits COX-2 expression by a G-protein independent mechanism to regulate inflammatory signaling in microglia and cancer cells. Identification of this novel mechanism will facilitate strategic targeting of RGS10 to develop new anti-inflammatory therapeutics.
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