Exogenous hydrogen sulfide donor NaHS alleviates nickel-induced epithelial-mesenchymal transition and the migration of A549 cells by regulating TGF-β1/Smad2/Smad3 signaling

Ye, Mengjuan; Yu, Mengping; Yang, Dalong; Li, Jiahui; Wang, Haopei; Chen, Feipeng; Yu, Hanning; Shen, Tong; Zhu, Qingsan; Zhou, Chengfan

doi:10.1016/j.ecoenv.2020.110464

Cited by 25 publications

(6 citation statements)

References 32 publications

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“…Nickel-exposure induced loss of E-cadherin expression has been observed in a number of previous studies. [10][11][12][13] Loss of E-cadherin expression is a critical step in EMT, 5 a key process in the development of chronic lung diseases such as asthma and fibrosis. 19 Moreover, reduced E-cadherin expression is often observed in epithelial cancers.…”

Section: Discussionmentioning

confidence: 99%

“…9 Downregulation of E-cadherin and EMT induction by nickel exposure has also been reported by other groups, as well. [10][11][12][13] Interestingly, our earlier studies showed that termination of nickel exposure did not reverse the loss of E-cadherin expression and the mesenchymal characteristics. This showed that nickel exposure could induce persistent mesenchymal phenotype.…”

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confidence: 91%

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Transcriptional repression of E‐cadherin in nickel‐exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter

Zhang

Tanwar

Jose

et al. 2021

Molecular Carcinogenesis

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E-cadherin plays a central role in the stability of epithelial tissues by facilitating cellcell adhesion. Loss of E-cadherin expression is a hallmark of epithelial-mesenchymal transition (EMT), a major event in the pathogenesis of several lung diseases. Our earlier studies showed that nickel, a ubiquitous environmental toxicant, induced EMT by persistently downregulating E-cadherin expression in human lung epithelial cells and that the EMT remained irreversible postexposure. However, the molecular basis of persistent E-cadherin downregulation by nickel exposure is not understood.Here, our studies show that the binding of transcription factor Sp1 to the promoter of E-cadherin encoding gene, CDH1, is essential for its expression. Nickel exposure caused a loss of Sp1 binding at the CDH1 promoter, resulting in its downregulation and EMT induction. Loss of Sp1 binding at the CDH1 promoter was associated with an increase in the binding of ZEB1 adjacent to the Sp1 binding site. ZEB1, an EMT master regulator persistently upregulated by nickel exposure, is a negative regulator of CDH1. CRISPR-Cas9-mediated knockout of ZEB1 restored Sp1 binding at the CDH1 promoter. Furthermore, ZEB1 knockout rescued E-cadherin expression and re-established the epithelial phenotype. Since EMT is associated with a number of nickel-exposure-associated chronic inflammatory lung diseases including asthma, fibrosis and cancer and metastasis, our findings provide new insights into the mechanisms associated with nickel pathogenesis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

Transcriptional repression of E‐cadherin in nickel‐exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter

Zhang

Tanwar

Jose

et al. 2021

Molecular Carcinogenesis

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“…Similarly, in thyroid cancer cells, 200 µM NaHS treatment inhibits migration activities by deactivating the PI3K/AKT/mTOR and MAPK pathways [127]. In lung cancer A549 cells, treatment with 100 µM NaHS significantly reduces nickel-induced EMT and migration by regulating TGF-ꞵ1 pathway [128]. Moreover, NaHS decreases the protein levels of MMP-2 in gastric cancer [39], and EMT-inducing snail (SNAI 1) in breast cancer [112].…”

Section: H 2 S Donor Inhibits Cell Migration and Invasionmentioning

confidence: 99%

Role of hydrogen sulfide donors in cancer development and progression

et al. 2021

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In recent years, a vast number of potential cancer therapeutic targets have emerged. However, developing efficient and effective drugs for the targets is of major concern. Hydrogen sulfide (H2S), one of the three known gasotransmitters, is involved in the regulation of various cellular activities such as autophagy, apoptosis, migration, and proliferation. Low production of H2S has been identified in numerous cancer types. Treating cancer cells with H2S donors is the common experimental technique used to improve H2S levels; however, the outcome depends on the concentration/dose, time, cell type, and sometimes the drug used. Both natural and synthesized donors are available for this purpose, although their effects vary independently ranging from strong cancer suppressors to promoters. Nonetheless, numerous signaling pathways have been reported to be altered following the treatments with H2S donors which suggest their potential in cancer treatment. This review will analyze the potential of H2S donors in cancer therapy by summarizing key cellular processes and mechanisms involved.

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“…Donation of H 2 S can be triggered by hydrolysis, reactive oxygen species (ROS), biological thiols, specific wavelengths of light, and enzymes [ 140 , 141 , 142 , 143 ]. Various H 2 S donors have been synthesized and tested preclinically to kill cancer cells at high doses and/or long-term exposure [ 131 , 133 , 135 , 144 , 145 , 146 , 147 ]. A slow-releasing H 2 S donor, GYY4137, enhances glucose uptake, glycolysis, and lactate production while decreasing the activity of pH regulators, anion exchanger (AE), and sodium/proton exchanger (NHE), resulting in the intracellular acidification in cancer cells [ 130 ].…”

Section: Hydrogen Sulfide Based Therapeuticsmentioning

confidence: 99%

The Hidden Role of Hydrogen Sulfide Metabolism in Cancer

Wang

Chu

Lin

2021

IJMS

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Hydrogen Sulfide (H2S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H2S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H2S plays various roles during cancer development reveals opportunities to target H2S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H2S-mediated protein persulfidation and the detailed information about the dysregulation of H2S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H2S-mediated cancer progression and summarize current options to modulate H2S production for cancer therapy.

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Exogenous hydrogen sulfide donor NaHS alleviates nickel-induced epithelial-mesenchymal transition and the migration of A549 cells by regulating TGF-β1/Smad2/Smad3 signaling

Cited by 25 publications

References 32 publications

Transcriptional repression of E‐cadherin in nickel‐exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter

Transcriptional repression of E‐cadherin in nickel‐exposed lung epithelial cells mediated by loss of Sp1 binding at the promoter

Role of hydrogen sulfide donors in cancer development and progression

The Hidden Role of Hydrogen Sulfide Metabolism in Cancer

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