Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells

Hooks, Shelley B.; Callihan, Phillip; Altman, Molly K.; Hurst, Jillian H.; Ali, Mourad W.; Murph, Mandi M.

doi:10.1186/1476-4598-9-289

Cited by 84 publications

(99 citation statements)

References 42 publications

(54 reference statements)

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“…2). P2RY8, CCR10 and RGS10, which were elevated in HCC tissues and their pair paracancerous tissues, have been reported to play roles in carcinoma [33][34][35] . Our data showed that ARRB1 was upregulated in human HCC tissues and its paracancerous tissues compared with normal liver tissues, but there was no significant difference between HCC tissues and paracancerous tissues, suggesting that ARRB1 may play an important role in hepatocellular carcinogenesis.…”

Section: Discussionmentioning

confidence: 98%

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

et al. 2015

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G-protein-coupled receptors (GPCR) constitute the largest known superfamily for signal transduction and transmission, and they control a variety of physiological and pathological processes. GPCR adaptor b-arrestins (ARRBs) play a role in cancerous proliferation. However, the effect of ARRBs in inflammation-mediated hepatocellular carcinogenesis is unknown. Here we show that ARRB1, but not ARRB2, is upregulated in inflammation-associated hepatocellular carcinoma (HCC) and paracancerous tissues in humans. A genotoxic carcinogen, diethylnitrosamine (DEN), significantly induces hepatic inflammation, TNF-a production and ARRB1 expression. Although ARRB1 deficiency does not affect hepatic inflammation and TNF-a production, it markedly represses hepatocellular carcinogenesis by suppressing malignant proliferation in DEN-treated mice. Furthermore, TNF-a directly induces hepatic ARRB1 expression and enhances ARRB1 interaction with Akt by binding to boost Akt phosphorylation, resulting in malignant proliferation of liver cells. Our data suggest that ARRB1 enhances hepatocellular carcinogenesis by inflammation-mediated Akt signalling and that ARRB1 may be a potential therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 98%

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

et al. 2015

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“…Thus, we questioned whether transfection with miR-30c-2 Ã could prime or synergize with chemotherapy to further reduce viability among chemoresistant ovarian cancer cells. We began these experiments using SKOV-3 cells, a cisplatin insensitive cell line, that requires much higher doses of cisplatin than sensitive cells to effectively eliminate proliferation in culture (25). Treating cells with cisplatin (2.5 mmol/L) shows a clear, visible difference in cell morphology between controls and cells with miR-30c-2 Ã (Fig.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

Jia

Eneh

Ratnaparkhe

et al. 2011

Molecular Cancer Research

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MicroRNAs (miRNAs) are small noncoding RNAs that function as master regulators of posttranscriptional gene expression with each miRNA negatively regulating hundreds of genes. Lysophosphatidic acid (LPA) is a mitogenic lipid present within the ovarian tumor microenvironment and induces LPA receptor activation and intracellular signaling cascades like ERK/MAPK, leading to enhanced cellular proliferation. Here, we show that in SKOV-3 and OVCAR-3 cells, LPA stimulation at concentrations ranging from 1 nmol/L to 20 mmol/L for 30 to 60 minutes increases miR-30c-2 Ã , and this effect is mediated through a combination of receptors because knock down of multiple LPA receptors is required for inhibition. The epidermal growth factor and platelet-derived growth factor also increase miR-30c-2 Ã transcript expression, suggesting a broader responsive role for miR-30c-2 Ã . Thus, we investigated the functional role of miR-30c-2 Ã through ectopic expression of synthetic miRNA precursors of mature miRNA or antagomir transfection and observed that microRNA-30c-2 Ã reduces, and the antagomir enhances, cell proliferation and viability in OVCAR-3, cisplatin-insensitive SKOV-3 and chemoresistant HeyA8-MDR cells. Ectopic expression of miR-30c-2 Ã reduces BCL9 mRNA transcript abundance and BCL9 protein. Consistent with this observation, miR-30c-2 Ã ectopic expression also reduced BCL9 luciferase reporter gene expression. In comparison with IOSE cells, all cancer cells examined showed increased BCL9 expression, which is consistent with its role in tumor progression. Taken together, this suggest that growth factor induced proliferation mediates a neutralizing response by significantly increasing miR-30c-2 Ã which reduces BCL9 expression and cell proliferation in SKOV-3 and OVCAR-3 cells, likely as a mechanism to regulate signal transduction downstream. Mol Cancer Res; 9(12); 1732-45. Ó2011 AACR.

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“…The expression of RGS proteins is not only spatially regulated per cell type and subcellular localization but also temporally regulated by mechanisms that induce or suppress RGS expression in response to specific cues or during pathological conditions. Examples include RGS2 downregulation in androgen-independent prostate cancer (Cao et al, 2006) and hypertension (Semplicini et al, 2006), the down-regulation of RGS10 and RGS17 in models of chemoresistance in ovarian cancer (Hooks et al, 2010), as well as the up-regulation of RGS17 in lung and prostate cancer (James et al, 2009;Bodle et al, 2013). Importantly, RGS transcript and protein levels may be independently regulated.…”

Section: Regulation Of Function Localization and Expressionmentioning

confidence: 99%

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

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells

Cited by 84 publications

References 42 publications

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

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

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