Involvement of the G-Protein-Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc-Like Acidic Microenvironment

Li, Hao; Liu, Huafei; Zhang, Ning; Zhu, Zemin

doi:10.1155/2020/1328436

Cited by 9 publications

(7 citation statements)

References 38 publications

(48 reference statements)

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“…Previous studies demonstrated that other MMPs are regulated by an acidic condition in different diseases. The expression levels of MMP3 and MMP13 were elevated under the degenerated intervertebral disc-like acidic condition 34 . MMP12 is also increased by extracellular acidosis in systemic sclerosis 35 .…”

Section: Discussionmentioning

confidence: 94%

Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis

Chen¹,

Ning²,

Song³

et al. 2022

Int. J. Biol. Sci.

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Background: Acidic microenvironment is a common physiological phenomenon in tumors, and is closely related to cancer development, but the effects of acidosis on pancreatic adenocarcinoma (PDAC) remains to be elucidated. Methods : Metabonomic assay and transcriptomic microarray were used to detect the changes of metabolites and gene expression profile respectively in acidosis-adapted PDAC cells. Wound healing, transwell and in vivo assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation assays were performed to determine cell proliferation. Results: The acidosis-adapted PDAC cells had stronger metastasis and proliferation ability compared with the control cells. Metabonomic analysis showed that acidosis-adapted PDAC cells had both increased glucose and decreased glycolysis, implying a shift to pentose phosphate pathway. The metabolic shift further led to the inactivation of AMPK by elevating ATP. Transcriptomic analysis revealed that the differentially expressed genes in acidosis-adapted cells were enriched in extracellular matrix modification and Hippo signaling. Besides, MMP1 was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway, but could be reduced by AMPK activator. Conclusion : The present study showed that metabolic reprogramming promotes proliferation and metastasis of acidosis-adapted PDAC cells by inhibiting AMPK/Hippo signaling, thus upregulating MMP1.

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Section: Discussionmentioning

confidence: 94%

Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis

Chen¹,

Ning²,

Song³

et al. 2022

Int. J. Biol. Sci.

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show abstract

“…Previous studies demonstrated that other MMPs are regulated by acidic condition in different diseases. The expression levels of MMP3 and MMP13 were elevated under the degenerated intervertebral disc-like acidic condition 33 . MMP12 is also increased by extracellular acidosis in systemic sclerosis 34 .…”

Section: Discussionmentioning

confidence: 94%

Metabolic Reprogramming Promotes Metastasis of Acidosis-Adapted Pancreatic Ductal Adenocarcinoma Cells Via AMPK/YAP/MMP1 Axis

Chen

Ning

Song

et al. 2021

Preprint

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Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Acidic microenvironment, namely acidosis, is closely related to cancer development and progression, but the regulatory mechanism remains to be elucidated. Methods We generated acidosis-adapted PDAC cells (PANC-1 and SW1990) by continuously culturing under pH 6.5 medium. Metabonomic assay (LC-MS and LC-MS) was used to detect the metabolites. Transcriptomic microarray was applied to reveal the gene expression profile. The in vivo metastatic potential was assessed by tail vein injection. Wound healing assay and transwell assay were applied to evaluate cell migration and invasion capacity. CCK8 and colony formation were performed to determine cell proliferation. Flow cytometry was used to test cell cycle and apoptosis. Results These acidosis-adapted PDAC cells had stronger invasion and migration ability, accompanied by increased EMT markers expression. In addition, the proliferation rate of acidosis-adapted PDAC cells increased while apoptosis decreased under acidic medium. Metabonomic analysis showed that the glycolysis and AMP was decreased, and ATP was increased in acidosis-adapted cells. The metabolic shift led to the inactivation of AMPK. Transcriptomic analysis revealed that the differentially expressed genes in acid-adapted cells were enriched in extracellular matrix modification, Hippo signaling and others. MMP1, a matrix metalloproteinase, was the most upregulated gene in acidosis-adapted cells, mediated by the YAP/TAZ pathway. Knockdown of MMP1 significantly reduced invasion and metastasis capacity of acidosis-adapted cells. The AMPK activator MK8722 could reduce both YAP and MMP1 level in acidosis-adapted PDAC cells. Conclusion Altogether, the present study showed that the metabolic reprogramming towards elevated ATP production promotes invasion and metastasis of acidosis-adapted PDAC cells via depressing AMPK/Hippo signaling, thus upregulating MMP1.

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“…Receptor activator of NFκB ligand was the important pathway involved in neurotrophins secretion by nucleus pulposus cells under the degenerated IVD-like acidic microenvironment 17 . We found that A2aR reduced when NP cells stimulated by IL-1β, meanwhile, cAMP and CREB downregulated but NFκB upregulated.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2a receptor mediate anti-inflammation and collagen protection via cAMP/CREB/NFκB pathway in nucleus pulposus cells

Fang

Cai

et al. 2022

Preprint

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Purpose of the study: Clinical and animal studies had indicated that both inflammation and extracellular matrix metabolism took part in intervertebral disk degeneration. In this study, we investigated the role of adenosine A2a receptor (A2aR) in intervertebral disk and intend to clarify its mechanism. Materials and methods Rat nucleus pulposus (NP) cells were cultured in complete medium, when cells proliferated to the third passage, cells were divided into different groups. Sterile PBS treated for control group, 10ng/ml IL-1β treated NP cells as experimental group, 10ng/ml IL-1β and 10µmol CGS-21680 were added into NP cells, NC siRNA, PKA siRNA and NFκB siRNA stimulated NP cells 24 hours respectively then treated with IL-1β and CGS-21680. Cell proliferation and inflammatory cytokines, collagen, A2aR and their signaling molecules were evaluated. Results IL-1β induced inflammatory cytokine (IL-6 and TNF-α) released and collagen degrading protease (MMP3) overexpression, and A2aR was decreased in NP cells. Protein expression of cAMP, PKA and CREB were decreased, but NFκB was increased. These changes could be reversed by A2aR agonist (CGS-21680). Inflammatory cytokine, MMP3 and NFκB were upregulated in NP cells treated by PKA siRNA, but collagen II was downregulated. Inflammatory cytokine and MMP3 were downregulated in NFκB siRNA treated NP cells, while the expression of collagen II increased. Conclusion Our study hinted that IL-1β induced inflammation and collagen degradation through A2aR, A2aR was a protective receptor. CGS-21680 as the A2aR agonist could alleviate the damage caused by IL-1β. A2aR regulated inflammation and collagen via cAMP-CREB-NFκB axis pathway in NP cells.

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Involvement of the G-Protein-Coupled Receptor 4 in the Increased Expression of RANK/RANKL/OPG System and Neurotrophins by Nucleus Pulposus Cells under the Degenerated Intervertebral Disc-Like Acidic Microenvironment

Cited by 9 publications

References 38 publications

Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis

Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis

Metabolic Reprogramming Promotes Metastasis of Acidosis-Adapted Pancreatic Ductal Adenocarcinoma Cells Via AMPK/YAP/MMP1 Axis

Adenosine A2a receptor mediate anti-inflammation and collagen protection via cAMP/CREB/NFκB pathway in nucleus pulposus cells

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