An endogenous and ectopic expression of metabotropic glutamate receptor 8 (mGluR8) inhibits proliferation and increases chemosensitivity of human neuroblastoma and glioma cells

Jantas, Danuta; Grygier, Beata; Gołda, Sławomir; Chwastek, Jakub; Zatorska, Justyna; Tertil, Magdalena

doi:10.1016/j.canlet.2018.06.004

Cited by 14 publications

(11 citation statements)

References 76 publications

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“…It should be underlined that RA-differentiated cells are more suitable for monitoring of neurite outgrowth than undifferentiated ones (Lee et al 2015;Miloso et al 2004). Finally, we confirmed in RA-SH-SY5Y cells the H 2 O 2 potency to induce ICE-like protease, caspase-1 activity (Jantas et al 2018a) which was significantly attenuated only by Nec-1 + Curc combination (Table 3). Activation of this enzyme participates in another form of cell damage, namely pyroptosis (Espinosa-Oliva et al 2019;Wang et al 2019).…”

Section: Discussionsupporting

confidence: 55%

“…Moreover, we measured caspase-3 and caspase-1 activities in RA-SH-SY5Y cells after 9 and 18 h of treatment with Nec-1 (20 μM), Curc (5 μM), and H 2 O 2 (0.5 mM). Caspase-1 activity was measured according to a similar procedure as caspase-3 but with a different substrate (Ac-YVAD-AMC, 50 μM) and inhibitor (Ac-YVAD-CHO, 20 μM) as described previously (Jantas et al 2018a). The data (expressed as mean relative fluorescence units, RFU) first were normalized to protein level (measured by BCA method) and next calculated as a percent of vehicle-treated cells and presented as the mean ± SEM from 2 to 3 separate experiments with 2 repetitions each.…”

Section: Caspase-3 and Caspase-1 Activity Assaysmentioning

confidence: 99%

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Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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Necroptosis, a recently discovered form of non-apoptotic programmed cell death, can be implicated in many pathological conditions including neuronal cell death. Moreover, an inhibition of this process by necrostatin-1 (Nec-1) has been shown to be neuroprotective in in vitro and in vivo models of cerebral ischemia. However, the involvement of this type of cell death in oxidative stress-induced neuronal cell damage is less recognized. Therefore, we tested the effects of Nec-1, an inhibitor of necroptosis, in the model of hydrogen peroxide (H 2 O 2)-induced cell damage in human neuroblastoma SH-SY5Y and murine hippocampal HT-22 cell lines. The data showed that Nec-1 (10-40 μM) attenuated the cell death induced by H 2 O 2 in undifferentiated (UN-) and neuronal differentiated (RA-) SH-SY5Y cells with a higher efficacy in the former cell type. Moreover, Nec-1 partially reduced cell damage induced by 6-hydroxydopamine in UN-and RASH -SY5Y cells. The protective effect of Nec-1 was of similar magnitude as the effect of a caspase-3 inhibitor in both cell phenotypes and this effect were not potentiated after combined treatment. Furthermore, the non-specific apoptosis and necroptosis inhibitor curcumin augmented the beneficial effect of Nec-1 against H 2 O 2-evoked cell damage albeit only in RASH -SY5Y cells. Next, it was found that the mechanisms of neuroprotective effect of Nec-1 against H 2 O 2induced cell damage in SH-SY5Y cells involved the inhibition of lysosomal protease, cathepsin D, but not caspase-3 or calpain activities. In HT-22 cells, Nec-1 was protective in two models of oxidative stress (H 2 O 2 and glutamate) and that effect was blocked by a caspase inhibitor. Our data showed neuroprotective effects of the necroptosis inhibitor, Nec-1, against oxidative stress-induced cell damage and pointed to involvement of cathepsin D inhibition in the mechanism of its action. Moreover, a cell type-specific interplay between necroptosis and apoptosis has been demonstrated.

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Section: Discussionsupporting

confidence: 55%

Section: Caspase-3 and Caspase-1 Activity Assaysmentioning

confidence: 99%

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

et al. 2020

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“…It was reported that the inhibition of HIF-1α interfered the VM formation by downregulating VE-cadherin (46,47). Hypoxic conditions are commonly achieved by provision of 1% oxygen (48). Apart from the traditional method for the creation of hypoxic conditions, we also induced hypoxia by adding CoCl 2, and confirmed it by expressing HIF-1α in breast cancer cells.…”

Section: Il-1β Initiates Vascular Events Which Can Advance Cancer Cells To Undergo Vmsupporting

confidence: 61%

IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways

et al. 2021

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Vasculogenic mimicry (VM), a micro vessel-like structure formed by the cancer cells, plays a pivotal role in cancer malignancy and progression. Interleukin-1 beta (IL-1β) is an active pro-inflammatory cytokine and elevated in many tumor types, including breast cancer. However, the effect of IL-1β on the VM of breast cancer has not been clearly elucidated. In this study, breast cancer cells (MCF-7 and MDA-MB-231) were used to study the effect of IL-1β on the changes that can promote VM. The evidence for VM stimulated by IL-1β was acquired by analyzing the expression of VM-associated biomarkers (VE-cadherin, VEGFR-1, MMP-9, MMP-2, c-Fos, and c-Jun) via western blot, immunofluorescent staining, and Immunohistochemistry (IHC). Additionally, morphological evidence was collected via Matrigel-based cord formation assay under normoxic/hypoxic conditions and microvessel examination through Hematoxylin and Eosin staining (H&E). Furthermore, the STRING and Gene Ontology database was also used to analyze the VM-associated interacting molecules stimulated by IL-β. The results showed that the expression of VM biomarkers was increased in both MCF-7 and MDA-MB-231 cells after IL-1β treatment. The increase in VM response was observed in IL-1β treated cells under both normoxia and hypoxia. IL-1β also increased the activation of transcription factor AP-1 complex (c-Fos/c-Jun). The bioinformatics data indicated that p38/MAPK and PI3K/Akt signaling pathways were involved in the IL-1β stimulation. It was further confirmed by the downregulated expression of VM biomarkers and reduced formation of the intersections upon the addition of the signaling pathway inhibitors. The study suggests that IL-1β stimulates the VM and its associated events in breast cancer cells via p38/MAPK and PI3K/Akt signaling pathways. Aiming the VM-associated molecular targets promoted by IL-1β may offer a novel anti-angiogenic therapeutic strategy to control the aggressiveness of breast cancer cells.

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“…GRM8 encodes MGLUR8, a G-protein coupled glutamate receptor reported to significantly influence the risk of diseases affecting the CNS including behavior, mental disorder, cognition as well as tumorigenesis of the CNS and other systems (28)(29)(30). Of note, GRM8 expression has been shown to characterize Group 4 MB (47) which overlaps in molecular features with Group 3 tumors.…”

Section: Discussionmentioning

confidence: 99%

“…The marker genes of this specific cluster were selected, followed by validation and selection, performed with tumor samples from 33 patients with Group 3 MB. Consequently, we unearthed the GRM8 gene, encoding metabotropic glutamate receptor 8 (MGLUR8), a G-protein coupled glutamate receptor reported to significantly influence the risk of central nervous system (CNS) disease (28)(29)(30), and the AP1S2 gene, encoding AP-1 complex subunit sigma-2, a component of adaptor protein complex 1 and correlating with CNS disorder (31), as novel hallmarks linked to poor prognosis of Group 3 MB. Thus, our findings identified GRM8 and AP1S2 as potential targets for treatment of patients with MYC+ Group 3 MB in the future.…”

Section: Introductionmentioning

confidence: 99%

Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics

Qin

Pan

et al. 2021

Front. Oncol.

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Medulloblastoma (MB) is a highly heterogeneous and one of the most malignant pediatric brain tumors, comprising four subgroups: Sonic Hedgehog, Wingless, Group 3, and Group 4. Group 3 MB has the worst prognosis of all MBs. However, the molecular and cellular mechanisms driving the maintenance of malignancy are poorly understood. Here, we employed high-throughput single-cell and bulk RNA sequencing to identify novel molecular features of Group 3 MB, and found that a specific cell cluster displayed a highly malignant phenotype. Then, we identified the glutamate receptor metabotropic 8 (GRM8), and AP-1 complex subunit sigma-2 (AP1S2) genes as two critical markers of Group 3 MB, corresponding to its poor prognosis. Information on 33 clinical cases was further utilized for validation. Meanwhile, a global map of the molecular cascade downstream of the MYC oncogene in Group 3 MB was also delineated using single-cell RNA sequencing. Our data yields new insights into Group 3 MB molecular characteristics and provides novel therapeutic targets for this relentless disease.

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An endogenous and ectopic expression of metabotropic glutamate receptor 8 (mGluR8) inhibits proliferation and increases chemosensitivity of human neuroblastoma and glioma cells

Cited by 14 publications

References 76 publications

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

Neuroprotective Effects of Necrostatin-1 Against Oxidative Stress–Induced Cell Damage: an Involvement of Cathepsin D Inhibition

IL-1β Promotes Vasculogenic Mimicry of Breast Cancer Cells Through p38/MAPK and PI3K/Akt Signaling Pathways

Novel Molecular Hallmarks of Group 3 Medulloblastoma by Single-Cell Transcriptomics

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