Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers

Abstract

Abstract. Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Gα protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17.

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

“…Underscoring this, SNVs in the first intron of the RGS17 gene (rs6901126, rs4083914, and rs9479510) are associated with lung cancer (You et al, 2009). RGS17 also is overexpressed in human liver cancer (Hayes and Roman, 2016). Furthermore, when ovarian cancer cells are treated with chemotherapeutic agents, there is a loss of RGS17 expression, suggesting a role for RGS17 in chemoresistance, perhaps by promoting cell survival via phosphatidylinositol 3-kinase/AKT signaling in these cells (Hooks et al, 2010;Hayes and Roman, 2016).…”

“…Smoking and substance dependence James et al, 2009;Yoon et al, 2012;Zhang et al, 2012;Hayes and Roman, 2016 RGS19 Heart, lung, brain, and Garzon et al, 2004;Kohara et al, 2008;Yang et al, 2016a RGS5 variants and neurologic disorders, such as schizophrenia and bipolar disorder (Campbell et al, 2008b;Smith et al, 2009), its role is best defined in the vasculature. In this work, RGS5 is expressed in arterial smooth muscle cells, and its expression is correlated with protection from hypertension and atherosclerosis (Holobotovskyy et al, 2013;Cheng et al, 2015;Daniel et al, 2016).…”

“…RGS17, also known as RGSZ2, demonstrates GAP activity for Gai/o, Gaz, and Gaq (Mao et al, 2004). In humans, RGS17 is expressed in the nucleus accumbens, hippocampus, and putamen, with highest Genetic Variation in Human RGS Proteins expression found in the cerebellum (Mao et al, 2004;Hayes and Roman, 2016). However, outside the brain, RGS17 has been reported to be overexpressed in human lung adenocarcinomas and prostate cancer (Mao et al, 2004;James et al, 2009;You et al, 2009).…”

“…RGS17 also is overexpressed in human liver cancer (Hayes and Roman, 2016). Furthermore, when ovarian cancer cells are treated with chemotherapeutic agents, there is a loss of RGS17 expression, suggesting a role for RGS17 in chemoresistance, perhaps by promoting cell survival via phosphatidylinositol 3-kinase/AKT signaling in these cells (Hooks et al, 2010;Hayes and Roman, 2016). Outside of RGS17 links to cancer, postmortem brain samples from patients with clinical depression show a decrease in RGS17 expression (Shelton et al, 2011;Hayes and Roman, 2016).…”

Development of a bimolecular luminescence complementation assay for RGS: G protein interactions in cells

“…RGS6 plays a role in doxorubicin mediated cardiotoxicity and cardiomyopathy, as well as cytotoxicity leading to cardiomyopathy and hepatic cirrhosis associated with chronic alcohol consumption, independent of Gα binding (Yang, Maity et al 2013, Stewart, Maity et al 2015). The role RGS proteins play in a variety of disease states has been recently reviewed by several groups (Hurst and Hooks 2009, Sjogren 2011, Stewart, Maity et al 2015, Hayes and Roman 2016). …”