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

Abstract

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 (TNF) 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 (PGE) 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 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 production in microglia. Furthermore, the elevated inflammatory signaling resulting from RGS10 loss was not affected by G inhibition, and a RGS10 mutant that is unable to bind activated G proteins was as effective as wild type in inhibiting TNF expression. Similarly, suppression of RGS10 in ovarian cancer cells enhanced TNF and COX-2 expression, and this effect did not require G 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.

Regulator of G protein signaling 10: Structure, expression and functions in cellular physiology and diseases

“…Consistent with these data, knockdown of RGS10 in BV2 cells enhances LPS-induced cyclooxygenase-2 (COX-2) expression and the release of its downstream effector, PGE2. Interestingly, amplification of LPS-stimulated TNF-α and COX-2 following microglial RGS10 suppression does not require Gαi activity [98]. Despite the importance of these results, the molecular mechanism underlying RGS10 regulation of microglial inflammatory signaling has not been clearly defined.…”

“…A recent study has demonstrated RGS10-mediated regulation of Inflammatory signaling in SKOV-3 ovarian cancer cells, where the expression of TNF-α and COX-2 is robustly enhanced following RGS10 knockdown compared to control cells. Interestingly, the effects of RGS10 suppression on TNF-α and COX-2 expressions are independent of amplified Gαi signaling [98]. Given the finding that RGS10 modulates survival and chemoresistance of ovarian cancer and regulates inflammatory mediators' expressions that have recently linked to ovarian cancer chemoresistance [126][127][128], further work is needed to investigate whether amplification of inflammatory signaling accounts for the enhanced survival and chemoresistance observed in RGS10-deficient ovarian cancer cells.…”

Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology

“…Further evidence of the potential for excessive NFκB activity to contribute to parkinsonian neurodegeneration comes from rodent and cell culture models deficient in the Regulator of G-Protein Signaling 10 (RGS10) [ 15 – 17 ]. RGS10 is highly expressed in central and peripheral myeloid cells where it acts as a negative regulator of inflammation through inhibition of NFκB activity [ 15 – 18 ]. These studies have shown that RGS10 loss globally, in microglia, in macrophages, and in neurons increases susceptibility to immune- and oxidative stress-mediated dopaminergic neurodegeneration [ 15 – 17 , 19 , 20 ].…”

miR‑199b‑5p mediates adriamycin‑induced podocyte apoptosis by inhibiting the expression of RGS10

“…Another major finding from the present study was the identification of RGS10 as a novel target gene of miR-199b-5p. RGS10 is one of the smallest members of the RGS family and it exerts various biological effects in multiple organs ( 19 , 28 ). It has been reported that ovarian cancer cell apoptosis is decreased following RGS10 knockdown ( 29 ).…”