RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein-Independent Mechanism
RGS10 Regulates the Expression of Cyclooxygenase-2 and Tumor Necrosis Factor Alpha through a G Protein-Independent Mechanism
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DOI：
10.1124/mol.118.111674
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发表时间：
2018-10-01
影响因子：
3.6
通讯作者：
Hooks, Shelley B.
中科院分区：
文献类型：
--
作者：
Alqinyah, Mohammed;Almutairi, Faris;Hooks, Shelley B.
G蛋白信号传导蛋白RGS 10的小调节因子是神经炎症和卵巢癌细胞存活的关键调节因子;然而，RGS 10在这些细胞中的功能机制尚不清楚，也没有与特定的G蛋白通路相关。RGS 10在小胶质细胞中高度富集，并且小胶质细胞中RGS 10表达的缺失放大了炎性细胞因子肿瘤坏死因子α（TNF α）的产生并增强了小胶质细胞诱导的神经毒性。RGS 10还调节卵巢癌细胞的细胞存活和化学抗性。环氧合酶-2（考克斯-2）介导的前列腺素E-2（PGE（2））等前列腺素的产生是神经炎症和癌症化疗耐药的关键因素，表明其可能参与两种细胞类型中的RGS 10功能，但RGS 10和考克斯-2之间的联系尚未报道。为了解决这些问题，我们完成了一项机制研究，以表征RGS 10对TNF α和考克斯-2的调节，并确定这些作用是否通过G蛋白依赖性机制介导。我们的数据首次表明，RGS 10表达的丧失显著提高了小胶质细胞中刺激的考克斯-2表达和PGE 2产生。此外，由RGS 10损失引起的升高的炎症信号传导不受G α（i）抑制的影响，并且不能结合活化的G蛋白的RGS 10突变体在抑制TNF α表达方面与野生型一样有效。同样，抑制卵巢癌细胞中的RGS 10可增强TNF α和考克斯-2的表达，并且这种作用不需要G（i）活性。总之，我们的数据有力地表明，RGS 10抑制考克斯-2表达的G蛋白非依赖性机制，以调节炎症信号在小胶质细胞和卵巢癌细胞。
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 alpha (TNF alpha) 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 alpha and COX-2 and to determine if these effects are mediated through a G protein-dependentmechanism. 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 G alpha(i) inhibition, and a RGS10 mutant that is unable to bind activated G proteins was as effective as wild type in inhibiting TNF alpha expression. Similarly, suppression of RGS10 in ovarian cancer cells enhanced TNF alpha 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.