Nickel‐induced VEGF expression via regulation of Akt, ERK1/2, NFκB, and AMPK pathways in H460 cells

Wang, Jui-Chin; Chen, Shih Yin; Wang, Meilin; Ko, Jiunn‐Liang; Wu, Chieh‐Lin; Chen, Ching-Chung; Lin, Hui-Wen; Chang, Yuan Yen

doi:10.1002/tox.22731

Cited by 18 publications

(21 citation statements)

References 33 publications

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“…Indeed, ERK/MAPK signaling was predicted in the IPA analysis for Ni NPs and NiCl 2 in our study ( Figure 5). Previous studies have also suggested a role for PI3K/Akt and ERK signaling followed by Vascular Endothelial Growth Factor (VEGF) expression as a response to Ni [9,28,29]. We also recently reported the secretion of VEGF in THP-1-derived macrophages following exposure to Ni and NiO NPs [30] and, in the present study on BEAS-2B cells, increased transcription of VEGFA was observed for NiCl 2 (see Figure 5).…”

Section: Discussionsupporting

confidence: 80%

Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl2

et al. 2020

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Production of nickel (Ni) and nickel oxide (NiO) nanoparticles (NPs) leads to a risk of exposure and subsequent health effects. Understanding the toxicological effects and underlying mechanisms using relevant in vitro methods is, therefore, needed. The aim of this study is to explore changes in gene expression using RNA sequencing following long term (six weeks) low dose (0.5 µg Ni/mL) exposure of human lung cells (BEAS-2B) to Ni and NiO NPs as well as soluble NiCl2. Genotoxicity and cell transformation as well as cellular dose of Ni are also analyzed. Exposure to NiCl2 resulted in the largest number of differentially expressed genes (197), despite limited uptake, suggesting a major role of extracellular receptors and downstream signaling. Gene expression changes for all Ni exposures included genes coding for calcium-binding proteins (S100A14 and S100A2) as well as TIMP3, CCND2, EPCAM, IL4R and DDIT4. Several top enriched pathways for NiCl2 were defined by upregulation of, e.g., interleukin-1A and -1B, as well as Vascular Endothelial Growth Factor A (VEGFA). All Ni exposures caused DNA strand breaks (comet assay), whereas no induction of micronuclei was observed. Taken together, this study provides an insight into Ni-induced toxicity and mechanisms occurring at lower and more realistic exposure levels.

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Section: Discussionsupporting

confidence: 80%

Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl2

et al. 2020

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“…ANGPTL4 has been recognized as an indicator of whether breast cancer will metastasise to the lung [29], and other studies have indicated that TGF-β primes breast tumours for the seeding of lung metastasis through ANGPTL4 by modulating endothelial integrity to mediate lung metastasis seeding [11]. In our recent investigation, NiCl 2 increased the level of integrin beta 3 (ITGB3) through TGF-β signalling [27]. In addition, Zhu et al indicated that tumour-derived ANGPTL4 interacts with integrins to elevate the O2 − /H 2 O 2 ratio, thus stimulating tumour development [30].…”

Section: Discussionmentioning

confidence: 74%

“…It has been demonstrated that NiCl 2 has high invasive potential, which promotes angiogenesis and the acquisition of a persistent mesenchymal phenotype in lung cancer cells, via different pathways [26][27][28]. ANGPTL4 has been recognized as an indicator of whether breast cancer will metastasise to the lung [29], and other studies have indicated that TGF-β primes breast tumours for the seeding of lung metastasis through ANGPTL4 by modulating endothelial integrity to mediate lung metastasis seeding [11].…”

Section: Discussionmentioning

confidence: 99%

Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis

Kang

Hsu

et al. 2020

IJMS

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Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.

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“…Recent reviewers found that VEGF could induce the activation of Akt, ERK1/2, NF-κB and AMPK pathways in H460 cells ( 19 ). These reviewers proposed VEGF binds to its receptor (VEGFR) to further induce the activation of the downstream signals in tumor endothelial cells, including the extracellular regulated protein kinases (ERK), NF-κB and threonine protein kinase (Akt)/mammalian target of rapamycin (mTOR) pathways.…”

Section: Discussionmentioning

confidence: 99%

Plumbagin inhibits tumor angiogenesis of gastric carcinoma in mice by modulating nuclear factor-kappa B pathway

Cheng-Qian¹,

Feng²,

Li³

et al. 2020

Transl Cancer Res TCR

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Background: We aimed to determine the mechanism of plumbagin on tumor growth of gastric carcinoma.Methods: Sixty BALB/c mice were treated with 200 µL SGC-7901 cells to establish gastric carcinoma xenograft and randomly divided into four groups: model group, low dose of plumbagin group (2 mg/kg), medium dose of plumbagin group (4 mg/kg) and high dose of plumbagin group (6 mg/kg). The tumor volume and weight were measured every week, and the ratio of anti-tumor was analyzed. The contents of vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2) in serum and tumor tissues were tested by enzyme linked immunosorbent assay (ELISA), immunohistochemistry and Western blot, respectively. The microvessel density (MVD) in tumor tissues was evaluated by immunohistochemistry and Western blot. The levels of nuclear factor-kappa B (NF-κB) p-p65/NF-κB p65, p-inhibitor of NF-κB (IκB)α/ IKBα, p-IκB kinase (IKK)/IKK in tumor tissues were also analyzed by Western blot.Results: Compared with model group, plumbagin treatment significantly suppressed the growth of tumor (P<0.05). The inhibition rate was 50.32% in high dose group (6 mg/kg). Furthermore, we found that the expressions of VEGF, VEGRF2 and MVD were obviously decreased in plumbagin treatment groups when compared to model group (P<0.05). Importantly, plumbagin treatment could down-regulate the levels of NF-κB p-p65/NF-κB p65, p-IKK/IKK and p-IKBα/IKBα in tumor tissues.Conclusions: Our study indicated that plumbagin might be an effective drug in inhibiting the tumor angiogenesis of gastric cancer and the mechanism of anti-tumor may be associated with NF-κB pathway.

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Nickel‐induced VEGF expression via regulation of Akt, ERK1/2, NFκB, and AMPK pathways in H460 cells

Cited by 18 publications

References 33 publications

Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl2

Transcriptome Profiling and Toxicity Following Long-Term, Low Dose Exposure of Human Lung Cells to Ni and NiO Nanoparticles—Comparison with NiCl2

Metformin Mitigates Nickel-Elicited Angiopoietin-Like Protein 4 Expression via HIF-1α for Lung Tumorigenesis

Plumbagin inhibits tumor angiogenesis of gastric carcinoma in mice by modulating nuclear factor-kappa B pathway

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