RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein-Independent Mechanism.
Mol Pharmacol
; 94(4): 1103-1113, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-30049816
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 α (TNFα) 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 E2 (PGE2) 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 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 stimulated COX-2 expression and PGE2 production in 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 as wild type in inhibiting TNFα expression. Similarly, suppression of RGS10 in ovarian cancer cells enhanced TNFα and COX-2 expression, and this effect did not require Gi 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor de Necrosis Tumoral alfa
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Proteínas de Unión al GTP
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Proteínas RGS
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Ciclooxigenasa 2
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Mol Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Georgia