RETRACTED ARTICLE: Oncogenic transformation of human lung bronchial epithelial cells induced by arsenic involves ROS-dependent activation of STAT3-miR-21-PDCD4 mechanism

Pratheeshkumar, Poyil; Son, Young‐Ok; Divya, Sasidharan Padmaja; Wang, Lei; Zhang, Zhuo; Shi, Xianglin

doi:10.1038/srep37227

Cited by 40 publications

(38 citation statements)

References 60 publications

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“…In addition to HIF-1α pathways, miRs also act as critical mediators of hypoxia signaling through other signaling pathways. Previous studies confirmed that activation of STAT3 regulates miR-21 expression, as there is a conserved STAT3-binding site locted in miR-21 genomic region 32 . Inhibition of the activation of STAT3 with the STAT3 inhibitor S3I-201 reduced the miR-21 expression, suggesting that p-STAT3 might work together with HIF-1α to induce the expression of miR-21 under hypoxia.…”

Section: Discussionmentioning

confidence: 57%

Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21

Liu¹,

Wu²,

Dai³

et al. 2017

J. Cancer

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Hypoxia is an inseparable component of the bone marrow (BM) microenvironment, accounting for aggressive tumor behavior and poor prognosis of multiple myeloma (MM). Gambogenic acid (GNA) has proven to be an attractive option for treatment of tumors due to its tumor suppressive activity. Herein, we found that GNA exhibits remarkable apoptotic activity against MM cells even under hypoxia. MicroRNA-21 (miR-21) has been found over-expressed in MM patients and associated with the occurrence and development of MM. Direct studies have shown that there is a functional link between hypoxia and miR-21 expression in multiple types of tumors. In the current study, we found that hypoxia increased miR-21 expression in U266 cells and miR-21 induced by hypoxia was associated with concurrent reductions in its target PTEN. After treatment with GNA, miR-21 expression in hypoxic U266 cells was strikingly downregulated in a dose-dependent manner. Besides, we identified that regulation of miR-21/PTEN by GNA under hypoxia is related with inhibition of HIF-1α accumulation and STAT3 phosphorylation. Furthermore, in vivo study revealed that intravenous GNA injection could significantly suppress tumor growth and the miR-21/PTEN pathway is involved in GNA's anti-tumor effects. Taken together, all these results indicated that GNA could be a highly potent therapeutic for human MM.

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Section: Discussionmentioning

confidence: 57%

Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21

Liu¹,

Wu²,

Dai³

et al. 2017

J. Cancer

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“…Experiment was performed in triplicate and representative results are shown here. *P < 0.05 and #P < 0.01, compared with control and 0.5 μM) for 6 months (Pratheeshkumar et al, 2016) and 0.25 μM arsenite for 16 weeks (Zhang et al, 2012). Another study showed that human bronchial epithelial cells were malignantly transformed after exposure to 1.0 μM arsenite for about 15 weeks .…”

Section: Discussionmentioning

confidence: 96%

“…Consistently, Zhang et al () found that 0.25 μ m arsenite induced BEAS‐2B cell transformation after 24 weeks of exposure. BEAS‐2B cells could also be malignantly transformed after chronic exposure to low concentrations of arsenite (0.1, 0.25 and 0.5 μ m ) for 6 months (Pratheeshkumar et al, ) and 0.25 μ m arsenite for 16 weeks (Zhang et al, ). Another study showed that human bronchial epithelial cells were malignantly transformed after exposure to 1.0 μ m arsenite for about 15 weeks (Xu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Arsenite downregulates H3K4 trimethylation and H3K9 dimethylation during transformation of human bronchial epithelial cells

Yin

Xie

et al. 2017

J of Applied Toxicology

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Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic-induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS-2B) cells. After 16 weeks' exposure, cells were transformed by 0.1, 0.5 and 1 μm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 μm arsenite at 12 weeks, and 0.5 and 1 μm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A. Global dimethylated H3K9 (H3K9me2) was also decreased after exposure to 0.5 μm arsenite for 4, 8, 12 and 16 weeks and 1.0 μm arsenite for 8 and 12 weeks, which was associated with an increase of HDM activities. Our findings indicated that arsenite decreased global H3K4me3 and H3K9me2 levels during cell transformation by modulating the enzymatic activities of histone methyltransferases and/or HDMs, and by upregulation of KDM5A protein levels for H3K4me3.

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“…Multiple mechanisms have been described for arsenic mode of action. Many studies have reported increased generation of reactive oxygen and nitrogen species (ROS/RNS) as a result of cellular arsenic metabolism and induction of NADPH oxidase activity (16)(17)(18)(19). It has also been reported that arsenic-induced ROS deplete glutathione pools, cause oxidative modifications to lipids and proteins, affect mitochondrial integrity and function, and result in mutations or chromosomal aberrations, which may be exacerbated by the arsenic-mediated inhibition of DNA repair enzymes (20)(21)(22)(23).…”

mentioning

confidence: 99%

“…Metabolic conversion of arsenic to methylated forms consumes S-adenosylmethionine (SAM), a methyl group donor necessary for DNA and histone methylation (25). Moreover, recent studies have correlated arsenic exposure to alterations in microRNA (miRNA) expression (17,26).…”

mentioning

confidence: 99%

Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction

Dodson

Liu

Jiang

et al. 2018

Molecular and Cellular Biology

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Environmental exposure to arsenic is linked to adverse health effects including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here, we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation defective, but not wild type, SNAP29 into CRISPR-mediated knockout cells abolishes arsenic-mediated autophagy inhibition. These findings reveal a mechanism by which low-levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic.

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RETRACTED ARTICLE: Oncogenic transformation of human lung bronchial epithelial cells induced by arsenic involves ROS-dependent activation of STAT3-miR-21-PDCD4 mechanism

Cited by 40 publications

References 60 publications

Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21

Gambogenic Acid Exerts Antitumor Activity in Hypoxic Multiple Myeloma Cells by Regulation of miR-21

Arsenite downregulates H3K4 trimethylation and H3K9 dimethylation during transformation of human bronchial epithelial cells

Increased O-GlcNAcylation of SNAP29 Drives Arsenic-Induced Autophagic Dysfunction

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