Signaling mechanism of protease activated receptor 1-induced proliferation of astrocytes: Stabilization of hypoxia inducible factor-1α triggers glucose metabolism and accumulation of cyclin D1

Zhu, Zhihui; Reiser, Georg

doi:10.1016/j.neuint.2014.09.010

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…SIXAC influence on PAR1 was indirectly measured via the pERK/ERK2 ratio. PAR1 activation is known to induce proliferation in astrocytes via MAPK involving multiple signaling pathways (46).…”

Section: Discussionmentioning

confidence: 99%

A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma

et al. 2018

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Data from human biopsies, in-vitro and in-vivo models, strongly supports the role of thrombin, and its protease-activated receptor (PAR1) in the pathology and progression of glioblastoma (GBM), a high-grade glial tumor. Activation of PAR1 by thrombin stimulates vasogenic edema, tumor adhesion and tumor growth. We here present a novel six amino acid chloromethyl-ketone compound (SIXAC) which specifically inhibits PAR1 proteolytic activation and counteracts the over-activation of PAR1 by tumor generated thrombin. SIXAC effects were demonstrated in-vitro utilizing 3 cell-lines, including the highly malignant CNS-1 cell-line which was also used as a model for GBM in-vivo. The in-vitro effects of SIXAC on proliferation rate, invasion and thrombin activity were measured by XTT, wound healing, colony formation and fluorescent assays, respectively. The effect of SIXAC on GBM in-vivo was assessed by measuring tumor and edema size as quantified by MRI imaging, by survival follow-up and brain histopathology. SIXAC was found in-vitro to inhibit thrombin-activity generated by CNS-1 cells (IC50 = 5 × 10−11M) and significantly decrease proliferation rate (p < 0.03) invasion (p = 0.02) and colony formation (p = 0.03) of these cells. In the CNS-1 GBM rat animal model SIXAC was found to reduce edema volume ratio (8.8 ± 1.9 vs. 4.9 ± 1, p < 0.04) and increase median survival (16 vs. 18.5 days, p < 0.02 by Log rank Mental-Cox test). These results strengthen the important role of thrombin/PAR1 pathway in glioblastoma progression and suggest SIXAC as a novel therapeutic tool for this fatal disease.

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Section: Discussionmentioning

confidence: 99%

A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma

et al. 2018

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“…Thrombin-activated PAR-1 and trypsin-activated PAR-2 receptors were found in cultured rat newborn astrocytes; activation of these receptors induced ER Ca 2+ release [400,401]. Astroglial PAR receptors are coupled to several signalling pathways, including stabilisation of hypoxia inducible factor-1α through ERK, JNK and PI3K/Akt cascades [436]. Activation of PAR-1 receptors (for example, by the selective peptide agonist TFLLR) is often used for selective stimulation of astroglia in situ [201,359], although there are reports of neuronal Ca 2+ signals triggered by the TFLLR-sensitive receptors [127].…”

Section: Protease-activated Receptors (Par)mentioning

confidence: 99%

Physiology of Astroglia

Verkhratsky

Parpura

Vardjan

et al. 2019

Advances in Experimental Medicine and Biology

254

340

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Astrocytes are principal cells responsible for maintaining the brain homeostasis. Additionally, these glial cells are also involved in homocellular (astrocyte-astrocyte) and heterocellular (astrocyte-other cell types) signalling and metabolism. These astroglial functions require an expression of the assortment of molecules, be that transporters or pumps, to maintain ion concentration gradients across the plasmalemma and the membrane of the endoplasmic reticulum. Astrocytes sense and balance their neurochemical environment via variety of transmitter receptors and transporters. As they are electrically non-excitable, astrocytes display intracellular calcium and sodium fluctuations, which are not only used for operative signalling but can also affect metabolism. In this chapter we discuss the molecules that achieve ionic gradients and underlie astrocyte signalling. Keywords Astrocytes; Brain homoeostasis; Neurotransmitter receptors; Ion channels; SLC transporters; Ca 2+ signaling; Na + signalling 3.1 Definition of Astroglia Astroglia (also known as astrocytes) are a class of neural cells of ectodermal, neuroepithelial origin that sustain homeostasis and provide for defence of the central nervous system (CNS) (Fig. 3.1; [410]). The term astrocyte (αστρoν κψτoσ; astron, star and kytos, a hollow A.

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“…In earlier studies the ERK½ signaling has been linked with PAR-1 downstream signaling and has been correlated with the pathogenesis of gliomas [31,32]. Activation of PAR-1 has been shown to induce proliferation in astrocytes via MAPK involving distinct signaling pathways [33]. Activation of PAR-1 by a synthetic peptide PAR-1 activator TFLLR led to an increased level of phospho ERK ½ in both D-54 MG and U-87 MG cells.…”

Section: Discussionmentioning

confidence: 99%

Higher expression of PAR-1 may be associated with severity of Glioblastomas

Tripathy

Singh

Siddiqui

et al. 2021

Preprint

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Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumors. Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor that elicits several pro-tumoral responses. It has been linked to proliferation and invasiveness in glioblastomas. In the present study, prevalence of the receptor (PAR-1) and its associated downstream signaling was studied in two human glioblastoma cell lines D-54 MG and U-87 MG. The expression of PAR1 was found to be significantly higher in D-54 MG cell-line when compared to U-87 MG cell-line. The activation of PAR-1 in the presence of TFLLR (a synthetic peptide activator of PAR-1) led to an increase in ERK ½ activity along with a significant increase in the migration and invasion of these cell-lines. Subsequent treatment with SCH-79797 (PAR-1 inhibitor) significantly decreased the migration and invasion in these glioma cell lines, respectively. The relative increase and decrease in the migration and invasion of these cell lines in presence of activator and inhibitor respectively was found to be linked with the expression of PAR-1. To conclude the study links the PAR-1 signaling with progression of Glioblastoma. PAR-1 and associated downstream signaling may be a potential therapeutic target to preclude the pathogenesis of gliomas.

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Signaling mechanism of protease activated receptor 1-induced proliferation of astrocytes: Stabilization of hypoxia inducible factor-1α triggers glucose metabolism and accumulation of cyclin D1

Cited by 11 publications

References 48 publications

A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma

A Novel Compound Targeting Protease Receptor 1 Activators for the Treatment of Glioblastoma

Physiology of Astroglia

Higher expression of PAR-1 may be associated with severity of Glioblastomas

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