Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway

Li, Qunyi; Zhu, Yiqian; Zhang, Meng; Chen, Li; Zhang, Zhen; Du, Yipeng; Ren, Guowu; Tang, Jianmin; Zhong, Mingkang; Shi, Xiaojin

doi:10.1016/j.ejphar.2015.01.046

Cited by 26 publications

(13 citation statements)

References 35 publications

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“…Additionally, Src has been shown to activate HIF1α by diverse pathways involving both direct as well as indirect mechanisms [53–55]. Therefore, we investigated if Src is involved in activating HIF1α and Slug.…”

Section: Resultsmentioning

confidence: 99%

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Ward

Radhakrishnan

et al. 2016

Oncotarget

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Recent studies have identified a critical role for lysophosphatidic acid (LPA) in the progression of ovarian cancer. Using a transcription factor activation reporter array, which analyzes 45 distinct transcription factors, it has been observed that LPA observed robustly activates the transcription factor hypoxia-induced factor-1α (HIF1α) in SKOV3.ip ovarian cancer cells. HIF1α showed 150-fold increase in its activation profile compared to the untreated control. Validation of the array analysis indicated that LPA stimulates a rapid increase in the levels of HIF1α in ovarian cancer cells, with an observed maximum level of HIF1α-induction by 4 hours. Our report demonstrates that LPA stimulates the increase in HIF1α levels via Gαi2. Consistent with the role of HIF1α in epithelial to mesenchymal transition (EMT) of cancer cells, LPA stimulates EMT and associated invasive cell migration along with an increase in the expression levels N-cadherin and Slug/Snail2. Using the expression of Slug/Snail2 as a marker for EMT, we demonstrate that the inhibition of Gαi2, HIF1α or Src attenuates this response. In line with the established role of EMT in promoting invasive cell migration, our data demonstrates that the inhibition of HIF1α with the clinically used HIF1α inhibitor, PX-478, drastically attenuates LPA-stimulates invasive migration of SKOV3.ip cells. Thus, our present study demonstrates that LPA utilizes a Gαi2-mediated signaling pathway via Src kinase to stimulate an increase in HIF1α levels and downstream EMT-specific factors such as Slug, leading to invasive migration of ovarian cancer cells.

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Section: Resultsmentioning

confidence: 99%

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Ward

Radhakrishnan

et al. 2016

Oncotarget

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“…The cell cycle is a highly regulated process that involves a complex cascade of events to regulate cell proliferation (21)(22)(23). It comprises three distinct phases: The G0/G1 phase, the DNA synthesis-associated S phase and the G2/M phase (23,24).…”

Section: Discussionmentioning

confidence: 99%

Icariin inhibits oxidized low-density lipoprotein-induced proliferation of vascular smooth muscle cells by suppressing activation of extracellular signal-regulated kinase 1/2 and expression of proliferating cell nuclear antigen

Liu

Yan

et al. 2016

Molecular Medicine Reports

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Icariin, a flavonoid isolated from the traditional Chinese herbal medicine Epimedium brevicornum Maxim, has been shown to possess anti-inflammatory, anti‑oxidant and anti-atherosclerotic activities in vivo and in vitro. The aim of the present study was to investigate the effects of icariin on oxidized low‑density lipoprotein (ox-LDL)-induced proliferation of vascular smooth muscle cells (VSMCs) and the possible underlying mechanism. VSMCs were cultured and pre‑treated with various concentrations of icariin (0, 10, 20 or 40 µm) prior to stimulation by ox‑LDL (50 µg/ml). Cell proliferation was evaluated by an MTT assay. Flow cytometry was used to study the influence of icariin on the cell cycle. Proliferating cell nuclear antigen (PCNA) expression and phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2 were detected by western blot analysis. The results indicated that icariin significantly inhibited ox‑LDL‑induced proliferation of VSMCs and phosphorylation of ERK1/2. Furthermore, icariin also blocked the ox‑LDL‑induced cell‑cycle progression at G1/S‑interphase and downregulated the expression of PCNA in VSMCs. In conclusion, the present study indicated for the first time that icariin reduced the amount of ox‑LDL‑induced proliferation of VSMCs through suppression of PCNA expression and inactivation of ERK1/2.

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“…Inhibition of GRB2 function impairs developmental processes in various organisms and suppresses the transformation and proliferation of various cell types 32. GRB2 is well known for its role to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, which may explain its ability to enhance the proliferation of human cells 33.…”

Section: Discussionmentioning

confidence: 99%

Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells

Li¹,

Qian²,

Wang³

2017

COPD

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MicroRNA-124 (miR-124) has been reported to be downregulated in the cells exposed to hypoxia, which was confirmed in our study. We then used online microRNA target prediction tools to identify GRB2, SMAD5, and JAG1 as the candidate target genes of miR-124, and we next validated GRB2 as a direct gene by using luciferase reporter system. We also established the regulatory relationship between miR-124 and GRB2 by showing the negative linear relationship between GRB2 and miR-124 expression. Furthermore, we investigated the miR-124 and GRB2 expression levels of different genotypes including CC (n=30), GC (n=18), and GG (n=4), which supported the hypothesis that the presence of minor allele (C) of rs531564 polymorphism compromised the expression of miR-124. Meanwhile, we also conducted real-time polymerase chain reaction and Western blot analysis to study the expression of GRB2 among different genotypes or pulmonary artery smooth muscle cells (PASMCs) treated with miR-124 mimics, GRB2 small interfering RNA, and miR-124 inhibitors, respectively, and found that introduction of miR-124 or GRB2 small interfering RNA could reduce the expression of GRB2 and inhibit the proliferation of PASMCs, while miR-124 upregulated the expression of GRB2 and promoted the proliferation of PASMCs. A total of 412 COPD patients with PAH (n=182) or without PAH (n=230) were recruited in this study, and more individuals carrying at least one minor allele of rs531564 were found in the COPD patients with PAH than in those without PAH (odds ratio: 0.61, 95% confidence interval: 0.41–0.91; P=0.166). In conclusion, the presence of rs531564 minor allele may increase the risk of PAH in COPD by reducing miR-124 expression, increasing GRB2 expression, and promoting the proliferation of PASMCs.

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Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway

Cited by 26 publications

References 35 publications

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Lysophosphatidic acid stimulates epithelial to mesenchymal transition marker Slug/Snail2 in ovarian cancer cells via Gαi2, Src, and HIF1α signaling nexus

Icariin inhibits oxidized low-density lipoprotein-induced proliferation of vascular smooth muscle cells by suppressing activation of extracellular signal-regulated kinase 1/2 and expression of proliferating cell nuclear antigen

Pri-microRNA-124 rs531564 polymorphism minor allele increases the risk of pulmonary artery hypertension by abnormally enhancing proliferation of pulmonary artery smooth muscle cells

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