G protein-coupled receptors stimulation and the control of cell migration

Cotton, Mathieu; Claing, Audrey

doi:10.1016/j.cellsig.2009.02.008

Cited by 149 publications

(131 citation statements)

References 169 publications

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“…RGS proteins are linked to the initiation and progression of cancer (Hurst and Hooks, 2009). They serve as strong regulatory molecules that act as GTPase-activating proteins and thus shorten the duration and reduce the magnitude of heterotrimeric GPCR signalling that underlies a wide variety of cellular processes including cell motility (De Vries et al, 2000;Cotton and Claing, 2009). RGS4 is such a molecule that has previously been ascribed a role in controlling breast cancer cell invasiveness by disrupting Ras-related C3 botulinum toxin substrate (Rac)1-dependent lamellipodia formation.…”

Section: Discussionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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Section: Discussionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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“…Agonists binding to β-ARs activate signaling by receptor-coupled GTP binding proteins (G-proteins); downstream effectors include adenylyl cyclase, cyclic AMP, and c-SRC. And c-SRC participates in signal transduction mediated by the epidermal growth factor receptor (EGFR) tyrosine kinase and then leads to activation of the Akt and ERK1/2 pathways [28,29] . Moreover, HIF-1α expression and activity are regulated by major signal transduction pathways including Akt and ERK1/2 [7] .…”

Section: Discussionmentioning

confidence: 99%

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

Qing

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim: To examine whether β-adrenoceptor (β-AR) agonists can induce hypoxia-inducible factor (HIF)-1α accumulation which then upregulate the expression of its target genes in pancreatic cancer cells at normoxia, and to further elucidate the mechanism involved. Methods: Pulse-chase assay, RT-PCR, and Western blot were employed to detect the effects of β-AR agonists and antagonists, siRNA as well as several inhibitors of signal transduction pathways on MIA PaCa2 and BxPC-3 pancreatic cancer cells. Results: Treatment of pancreatic cancer cell lines with β-AR agonists led to accumulation of HIF-1α and then up-regulated expression of its target genes independently of oxygen levels. The induction was partly or completely inhibited not only by β-AR antagonists but also by inhibitors of PKA transduction pathways and by siHIF-1α. Both β1-AR and β2-AR agonists produced the above-mentioned effects, but β2-AR agonist was more potent. Conclusion: Activation of β-AR receptor transactivates epidermal growth factor receptor (EGFR) and then elicites Akt and ERK1/2 in a PKA-dependent manner, which together up-regulate levels of HIF-1α and downstream target genes independently of oxygen level. Our data suggest a novel mechanism in pancreatic cancer cells that links β-AR and HIF-1α signaling under normoxic conditions, with implications for the control of glucose transport, angiogenesis and metastasis.

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“…Emerging evidence shows that ␤Arr1 and ␤Arr2 also function as adaptors to transduce signals and to regulate a wide array of cellular functions, including actin remodeling and cell migration (11,12). One mechanism by which ␤Arrs regulate actin remodeling and cell migration is through regulation of monomeric G proteins, including RhoA, Cdc42, and RalA.…”

mentioning

confidence: 99%

βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

España‐Serrano

Kim

et al. 2014

Journal of Biological Chemistry

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Background: G protein-coupled receptors (GPCRs) and ␤arrestins have been shown to regulate cell motility. Results: ␤Arrestin1 regulates cell migration through RasGRF2 (a dual guanine nucleotide exchange factor) gene expression and the small GTPase Rac activity. Conclusion: ␤Arrestin1 may regulate cellular functions at the gene expression level. Significance: ␤Arrestins may function at transcriptional and post-translational levels to regulate cell migration.

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G protein-coupled receptors stimulation and the control of cell migration

Cited by 149 publications

References 169 publications

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

HIF-1α links β-adrenoceptor agonists and pancreatic cancer cells under normoxic condition

βArrestin1 Regulates the Guanine Nucleotide Exchange Factor RasGRF2 Expression and the Small GTPase Rac-mediated Formation of Membrane Protrusion and Cell Motility

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