G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

Liu, Huiqing; Xing, Rui; Ou, Zhimin; Zhao, Jintong; Hong, Guolin; Zhao, Tong‐Jin; Ying, Han; Chen, Ying

doi:10.1038/s41419-021-03897-0

Cited by 17 publications

(13 citation statements)

References 63 publications

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“…The combinatorial treatment increased the production of ROS with 3.5-fold change in MMK1 and approximately 3.0-fold in JK2 cells. This result agreed with the previous data, that the overexpression of GPR17 stimulates apoptosis by inducing ROS production and thereby inhibits glioma cell proliferation [35]. This data also suggested that THTMP + T0 was more efficient in inducing ROS-mediated apoptosis.…”

Section: Thtmp + T0 Activates Intrinsic Pathways Of Apoptosis Inductionsupporting

confidence: 93%

Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity

Doan

Nguyen

Murugesan

et al. 2021

Cells

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Drug resistance and tumor heterogeneity limits the therapeutic efficacy in treating glioblastoma, an aggressive infiltrative type of brain tumor. GBM cells develops resistance against chemotherapeutic agent, temozolomide (TMZ), which leads to the failure in treatment strategies. This enduring challenge of GBM drug resistance could be rational by combinatorial targeted therapy. Here, we evaluated the combinatorial effect of phenolic compound (2-(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol (THTMP), GPR17 agonist 2-({5-[3-(Morpholine-4-sulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-N-[4-(propan-2-yl)phenyl]acetamide (T0510.3657 or T0) with the frontline drug, TMZ, on the inhibition of GBM cells. Mesenchymal cell lines derived from patients’ tumors, MMK1 and JK2 were treated with the combination of THTMP + T0, THTMP + TMZ and T0 + TMZ. Cellular migration, invasion and clonogenicity assays were performed to check the migratory behavior and the ability to form colony of GBM cells. Mitochondrial membrane permeability (MMP) assay and intracellular calcium, [Ca2+]i, assay was done to comprehend the mechanism of apoptosis. Role of apoptosis-related signaling molecules was analyzed in the induction of programmed cell death. In vivo validation in the xenograft models further validates the preclinical efficacy of the combinatorial drug. GBM cells exert better synergistic effect when exposed to the cytotoxic concentration of THTMP + T0, than other combinations. It also inhibited tumor cell proliferation, migration, invasion, colony-forming ability and cell cycle progression in S phase, better than the other combinations. Moreover, the combination of THTMP + T0 profoundly increased the [Ca2+]i, reactive oxygen species in a time-dependent manner, thus affecting MMP and leading to apoptosis. The activation of intrinsic apoptotic pathway was regulated by the expression of Bcl-2, cleaved caspases-3, cytochrome c, HSP27, cIAP-1, cIAP-2, p53, and XIAP. The combinatorial drug showed promising anti-tumor efficacy in GBM xenograft model by reducing the tumor volume, suggesting it as an alternative drug to TMZ. Our findings indicate the coordinated administration of THTMP + T0 as an efficient therapy for inhibiting GBM cell proliferation.

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Section: Thtmp + T0 Activates Intrinsic Pathways Of Apoptosis Inductionsupporting

confidence: 93%

Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity

Doan

Nguyen

Murugesan

et al. 2021

Cells

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“…Glioma, the most common type of brain tumor, has been divided into four groups based on malignancies [ 108 ]. Glioblastoma (GBM), also known as grade IV glioma, is one of the most aggressive forms of cancer [ 109 ].…”

Section: Brain and Nerve Tumorsmentioning

confidence: 99%

“…KLF9 decreased the expression of SOD1 , a protein needed for ROS clearance ( Figure 7 (1B)). Upregulation of GPR17 also decreased cAMP levels, indicating that glycolysis and lactate production were also decreased [ 108 , 114 ].…”

Section: Brain and Nerve Tumorsmentioning

confidence: 99%

SP and KLF Transcription Factors in Cancer Metabolism

Orzechowska-Licari

LaComb

Mojumdar

et al. 2022

IJMS

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Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic pathways such as glycolysis, oxidative phosphorylation, lipid metabolism, and hexosamine biosynthesis pathway are crucial to sustain increased redox, bioenergetic, and biosynthesis demands of a tumor cell. Transcription factors (oncogenes and tumor suppressors) play crucial roles in modulating these alterations, and their functions are tethered to major metabolic pathways under homeostatic conditions and disease initiation and advancement. Specificity proteins (SPs) and Krüppel-like factors (KLFs) are closely related transcription factors characterized by three highly conserved zinc fingers domains that interact with DNA. Studies have demonstrated that SP and KLF transcription factors are expressed in various tissues and regulate diverse processes such as proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. This review highlights the role of SP and KLF transcription factors in the metabolism of various cancers and their impact on tumorigenesis. A better understanding of the role and underlying mechanisms governing the metabolic changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment.

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“…Of note, glioma cell development has been concomitantly linked to aberrant activation of WNT signaling and dysregulation of GPR17 expression: WNT pathway genes overexpression has been associated with increased tumor growth and invasion via the maintenance of stemness leading to a poor prognosis in glioma patients; on the contrary, GPR17 levels in tumor samples are reduced, and its activation inhibits glioma formation. Thus the balance between WNT and GPR17 might be dysregulated in glioma [14,15] .…”

Section: Introductionmentioning

confidence: 99%

G protein-coupled receptor 17 is regulated by WNT pathway during oligodendrocyte precursor cell differentiation

Boccazzi

Macchiarulo

Lebon

et al. 2023

Preprint

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G protein-coupled receptor 17 (GPR17) and the WNT pathway are critical players of oligodendrocyte (OL) differentiation acting as essential timers in developing brain to achieve fully-myelinating cells. However, whether and how these two systems are related to each under is still unknown. Of interest, both factors are dysregulated in developing and adult brain diseases, including demyelination disorders and cancer, making the understanding of their reciprocal interactions of potential importance for identifying new targets and strategies for myelin repair. Here, we examined regulatory mechanisms linking WNT signalling to GPR17 expression in OLs. We analyzed the relative expressions of mRNAs encoding GPR17 and the T cell factor/Lymphoid enhancer-binding factor-1 (TCF/LEF) transcription factors of the canonical WNT/b-CATENIN pathway in both PDGFRa+ and O4+ OLs during mouse post-natal development. In O4+ cells, Gpr17mRNA level peaked at post-natal day 14 and then decreased concomitantly to the physiological uprise of WNT tone, as shown by increasedLef1 mRNA level. The link between WNT signaling and GPR17 expression was further reinforced in vitro in primary PDGFRa+ cells and in the Oli-neu cell line. High WNT tone impaired OL differentiation and drastically reduced GPR17 mRNA and protein levels. In Oli-neu cells, we demonstrated that WNT/b-CATENIN activation represses Gpr17 promoter activity through both putative WNT response elements (WRE) and upregulation of the inhibitor of DNA-binding protein 2 (Id2). We conclude that WNT pathway influences oligodendrocyte maturation by repressing GPR17 which could have implications in pathologies characterized by dysregulations of the oligodendroglial lineage including multiple sclerosis and oligodendroglioma.

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G-protein-coupled receptor GPR17 inhibits glioma development by increasing polycomb repressive complex 1-mediated ROS production

Cited by 17 publications

References 63 publications

Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity

Alkylaminophenol and GPR17 Agonist for Glioblastoma Therapy: A Combinational Approach for Enhanced Cell Death Activity

SP and KLF Transcription Factors in Cancer Metabolism

G protein-coupled receptor 17 is regulated by WNT pathway during oligodendrocyte precursor cell differentiation

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