GPR50 Promotes Hepatocellular Carcinoma Progression via the Notch Signaling Pathway through Direct Interaction with ADAM17

Saha, Subbroto Kumar; Choi, Hye Yeon; Yang, Gwang-Mo; Biswas, Polash Kumar; Kim, Kyeongseok; Kang, Geun-Ho; Gil, Minchan; Cho, Ssang-Goo

doi:10.1016/j.omto.2020.04.002

“…In addition, Notch signalling was implicated in the ADAM17-dependent activation of integrin β1, thereby promoting the proliferation, migration and invasion of HCC cells [ 94 ]. In the context of these new findings, a new G-protein-coupled receptor 50 (GPR50)-mediated regulation of ADAM17-induced Notch signalling in HCC progression was also demonstrated [ 95 ]. Data collected so far suggest that ADAMs have been implicated at all stages of HCC progression, starting from inflammation and subsequently through to fibrosis, angiogenesis, proliferation, EMT and invasion ( Figure 4 ).…”

Section: Mechanism Of Adam17 Signals Modulation In Fibrotic Diseases and Cancermentioning

confidence: 99%

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

Sisto

¹

,

Ribatti

²

,

Lisi

³

2021

JCM

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For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

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“…It has been shown that GPR50 interacts with Gi and inhibits cAMP production in GPR50-overexpressing HEK293T cells ( Levoye et al, 2006 ; Hand, 2012 ). Interestingly, GPR50 is down-regulated in breast, cervical, ovarian and lung cancers while up-regulated in liver cancer ( Wojciech et al, 2018 ; Saha et al, 2020 ). Hence, GPR50-cAMP signaling pathway is a promising cancer drug target and screening ligands for GPR50 is of great importance.…”

Section: Resultsmentioning

confidence: 99%

An Improved Genetically Encoded Fluorescent cAMP Indicator for Sensitive cAMP Imaging and Fast Drug Screening

Liu

¹

,

Liu

²

,

Ren

³

et al. 2022

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Cyclic adenosine 3′,5′-monophosphate (cAMP) is an important intracellular second messenger molecule downstream of many G protein-coupled receptors (GPCRs). Fluorescence imaging with bright and sensitive cAMP indicators allows not only dissecting the spatiotemporal dynamics of intracellular cAMP, but also high-content screening of compounds against GPCRs. We previously reported the high-performance circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1. Here, we developed improved G-Flamp1 variants G-Flamp2 and G-Flamp2b. Compared to G-Flamp1, G-Flamp2 exhibited increased baseline fluorescence (1.6-fold) and larger fluorescence change (ΔF/F0) (1,300% vs. 1,100%) in HEK293T cells, while G-Flamp2b showed increased baseline fluorescence (3.1-fold) and smaller ΔF/F0 (400% vs. 1,100%). Furthermore, live cell imaging of mitochondrial matrix–targeted G-Flamp2 confirmed cytosolic cAMP was able to enter the mitochondrial matrix. G-Flamp2 imaging also showed that adipose tissue extract activated the Gi protein-coupled orphan GPCR GPR50 in HEK293T cells. Taken together, our results showed that the high-performance of G-Flamp2 would facilitate sensitive intracellular cAMP imaging and activity measurement of compounds targeting GPCR-cAMP signaling pathway during early drug development.

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“…Although sorafenib has been approved for clinical treatment, the severe side effects impede its long-term use [ 37 , 38 ]. Moreover, sorafenib resistance is emerging clinically, and meanwhile, it has been evidenced that the disruption of Notch/Akt signaling could drive malignant behaviors and drug resistance in many cancers [ 39 , 40 ]. Thus, finding novel antitumor drugs targeting Notch/Akt signaling is a growing concern.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effect of Pseudolaric Acid B Involving Regulation of Notch1/Akt Signaling Response in Human Hepatoma Cell In Vitro

Gao

¹

,

Zhang

²

,

Mo

³

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Liver cancer, particularly hepatocellular carcinoma (HCC), is the fourth leading cause of cancer-related death worldwide. Sorafenib is a crucial drug for the treatment of advanced HCC, but it is difficult to meet the challenge of increasing clinical demands due to its severe side effects and drug resistance. Hence, development of novel antitumor drugs is urged. Previous studies showed that pseudolaric acid B (PAB) could reduce the expression of protein kinase B (PKB/Akt), a downstream effector of Notch signaling, facilitating cell apoptosis in HCC. The disruption of Notch signaling was verified to exacerbate malignant progression and drug resistance, however, the antitumor effect of PAB on Notch signaling in HCC remains unclear. Thus, this study aims to investigate the anti-HCC effect of PAB in association with the regulation of Notch1/Akt signaling. Methods. CCK-8 assay and transwell assay were used to examine the cell proliferation and invasion in Huh7 cells after treatment with PAB and a Notch inhibitor DAPT. Moreover, the cell cycle of Huh7 cells after treatment with PAB was analyzed using flow cytometry. Finally, the changes of Notch1, Jagged1, Hes1, and Akt expression at the protein and mRNA level in Notch1/Akt signaling in Huh7 cells after treatment with PAB and DAPT were analyzed using immunofluorescence assay and real-time qPCR. Results. The proliferation rate of Huh7 cells exposed to PAB of 0.5, 1, 2, 4, 8, 10, 20, 40, 80, 100, and 200 μmol/L revealed a time-and dose-dependent decrease in vitro, showing cell cycle arrest at G2/M phase P < 0.05 . Furthermore, compared with the untreated group, at the concentration of 40 μmol/L, the proliferation rate and invasion rate of Huh7 cells in PAB, DAPT, and PAB-DAPT combination (PAB + DAPT) group were significantly decreased P < 0.05 , but the PAB + DAPT showed no synergistic antiproliferation and anti-invasion effect in comparison with PAB treatment alone P > 0.05 . In addition, compared with the untreated group, PAB and DAPT alone significantly downregulated the expression of Notch1, Jagged1, Hes1, Akt mRNA, or/and protein in Huh7 cells P < 0.05 , but there was no significant difference in synergistic downregulated effect between the PAB + DAPT group and the PAB group P > 0.05 . Conclusion. PAB can suppress proliferation and invasion of HCC cells through downregulating the expression of Notch1/Akt signaling protein and mRNA, and may be a potential novel antitumor drug candidate for the clinical treatment of HCC in the future.

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GPR50 Promotes Hepatocellular Carcinoma Progression via the Notch Signaling Pathway through Direct Interaction with ADAM17

Cited by 15 publications

References 95 publications

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

An Improved Genetically Encoded Fluorescent cAMP Indicator for Sensitive cAMP Imaging and Fast Drug Screening

Antitumor Effect of Pseudolaric Acid B Involving Regulation of Notch1/Akt Signaling Response in Human Hepatoma Cell In Vitro

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