RGS2 Suppresses Breast Cancer Cell Growth via a MCPIP1-Dependent Pathway

Abstract

Regulator of G protein signaling 2 (RGS2) is a member of a family of proteins that functions as a GTPase-activating protein (GAP) for Gα subunits. RGS2 mRNA expression is lower in breast cancerous tissues than in normal tissues. In addition, expression of RGS2 is also lower in MCF7 (cancerous breast cells) than in MCF10A (normal breast cells). Here we investigated whether RGS2 inhibits growth of breast cancer cells. RGS2 overexpression in MCF7 cells inhibited epidermal growth factor- or serum-induced proliferation. In HEK293T cells expressing RGS2, cell growth was also significantly suppressed (In addition, exogenous expression of RGS2 in HEK293T cells resulted in the significant suppression of cell growth). These results suggest that RGS2 may have a tumor suppressor function. MG-132 treatment of MCF7 cells increased endogenous or exogenous RGS2 levels, suggesting a post-transcriptional regulatory mechanism that controls RGS2 protein levels. RGS2 protein was degraded polyubiquitinated the K71 residue, but stabilized by deubiquitinase monocyte chemotactic protein-induced protein 1 (MCPIP1), and not affected by dominant negative mutant (C157A) of MCPIP1. Gene expression profiling study showed that overexpression of RGS2 decreased levels of testis specific Y encoded like protein 5 (TSPYL5), which plays a causal role in breast oncogenesis. TSPYL5 protein expression was low in MCF10A and high in MCF7 cells, showing the opposite aspect to RGS2 expression. Additionally, RGS2 or MCPIP1 overexpression in MCF7 cells decreased TSPYL5 protein level, indicating that RGS2 stabilized by MCPIP1 have diminished TSPYL5 protein levels, thereby exerting an inhibitory effect of breast cancer cell growth.

MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression

“…There is growing evidence that MCPIP1 plays a role during the process of tumorigenesis. It has been already demonstrated that MCPIP1 regulates the viability and proliferation of neuroblastoma (20), HeLa, HepG2 (19), ccRCC (25), and breast cancer cells (21). Previous findings have demonstrated that MCPIP1 degrades the mRNA of antiapoptotic gene transcripts in breast cancer cells, leading to apoptosis and tumor regression (22).…”

“…In addition, MCPIP1 is a negative regulator of NFkB activity (11,16,17) and may suppress miRNA biosynthesis (18). Recently, it has been shown that MCPIP1 is involved in the regulation of viability and proliferation in numerous cancer cell lines (19)(20)(21). Moreover, MCPIP1 overexpression in breast cancer cells induces apoptosis in vitro and reduces tumor growth and metastatic disease in vivo (22).…”

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

“…As discussed above, RGS2 is one of several RGS proteins that is rapidly degraded through the ubiquitin-proteasomal pathway. Low RGS2 protein levels are associated with hypertension and other cardiovascular pathologies (Heximer et al, 2003;Takimoto et al, 2009;Tsang et al, 2010) and could also be involved in the progression of prostate and breast cancer (Cao et al, 2006;Lyu et al, 2015). In our initial screen, we identified digoxin and other cardiotonic steroids as selective stabilizers of RGS2 protein levels (Sjögren et al, 2012).…”

Regulator of G-protein signaling 2 (RGS2) in cardiology and oncology

“…Muscarinic receptors are GPCRs (G protein-coupled receptors), and as such they activate heterotrimeric G proteins by catalyzing GDP dissociation from the Gα subunit and consequently promoting GTP binding [17,18]. Regulator of G-protein signaling 2 (RGS2) is a member of a large family of proteins that all regulate signaling through GPCRs by accelerating GTPase [19-21]-activity on active Gα as well as through other mechanisms.…”

“…In primary human airway smooth muscle cells, glucocorticoid/ long-acting β (2)-adrenoceptor agonist (LABA) combination synergistically induces the expression of RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens [37]. RGS2 mRNA expression is lower in breast cancerous tissues than in normal tissues and research suggests that its overexpression exerts an inhibitory effect of breast cancer cell growth [18]. RGS2 is specifically downregulated in androgen-independent prostate cancer cells (AIPCC) and research found that RGS2 functioned as a growth suppressor for AIPCC [85,86].…”