Suppression of NRF2/ARE by convallatoxin sensitises A549 cells to 5-FU-mediated apoptosis

Lee, June; Kang, Jong-Su; Nam, Le Ba; Yoo, Ok-Kyung; Keum, Young‐Sam

doi:10.1080/10715762.2018.1489132

Cited by 25 publications

(9 citation statements)

References 18 publications

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“…Furthermore, the depletion of NRF2 was found to inhibit the induction of apoptosis by KEAP1 depletion. Despite more and more studies investigating Nrf2/Keap1 modulated death of multiple cell lines, [32][33][34] Some other mechanisms associated with Nrf2 stimulation have been reported, including acetylation, phosphorylation, and cysteine post-translational modification. These modifications regulate activities of glycogen synthase kinase-3 beta (GSK3b), phosphatidylinositol 3-kinase pathway (PI3K/AKT), PKC, MAPK, as well as extracellular regulated protein kinases (ERKs).…”

Section: R E T R a Cmentioning

confidence: 99%

RETRACTED: Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

Zhang

Lian

et al. 2019

Exp Biol Med (Maywood)

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Type I diabetes mellitus (TIDM) serves as a large contributor to morbidity as well as mortality globally with persistently elevating prevalence. It is known that oxidative damage by free radicals participates in etiology, complications, as well as progression of TIDM. In our research, we demonstrate that Keap1-Nrf2-ARE pathway was stimulated by exendin-4 treatment during the development of type I diabetes in murine TIDM model as well as in pancreatic β-cells. We also observed excessive reactive oxygen species (ROS) production, low level of cell death, and PKC phosphorylation on exendine-4 treatment. Nrf2 knockdown led to suppression of ROS generation as well as increasing apoptosis. Moreover, siRNA-mediated Nrf2 down-regulation attenuated the suppressive effect of exendin-4 in pancreatic β-cell viability, through modulating apoptosis promoting- and counteracting-proteins, Bax, and Bcl-2. Thus, the present study indicates exendin-4 mediates activation of Keap1-Nrf2-ARE pathway and may serve as a promising agent to treat TIDM. Impact statement Nrf2 is an essential part of the defense mechanism of vertebrates and protects them from surrounding stress via participation in stimulated expression of detoxification as well as antioxidant enzymes. It also exerts a role in defending hosts from different stress in the environment, including reactive oxygen species. Our study investigates the role of exendin-4 on Nrf2 pathway as well as cell death in pancreatic β-cell and in non-obese diabetic mice. Result of study indicates exendin-4 mediates activation of Keap1-Nrf2-ARE pathway and may serve as a potential agent to treat type I diabetes mellitus. In our research, we observed excessive reactive oxygen species production, low level of cell death, and PKC phosphorylation on exendine-4 treatment. Nrf2 knockdown led to suppression of reactive oxygen species generation as well as increasing apoptosis. Moreover, siRNA-mediated Nrf2 down-regulation attenuated the suppressive effect of exendin-4 in pancreatic β-cell viability, via modulating apoptosis promoting- and counteracting-proteins, Bax, and Bcl-2.

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Section: R E T R a Cmentioning

confidence: 99%

RETRACTED: Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

Zhang

Lian

et al. 2019

Exp Biol Med (Maywood)

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“…Trypan blue exclusion assay also indicated that the viability of A549 and H1299 cells was unaffected by triptolide at concentrations up to 40 nM ( Supplementary Figure S1 ). We have previously identified that convallatoxin inhibits NRF2 and sensitizes A549 cells to cisplatin-induced apoptosis ( Lee et al, 2018a ). Using convallatoxin as a prototypical NRF2 inhibitor, we exposed A549 cells to triptolide, and examined the expression of NRF2 and its target proteins, heme oxygenase-1 (HO-1) and NAD [P]H:quinone oxidoreductase-1 (NQO1) by Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

Triptolide Downregulates the Expression of NRF2 Target Genes by Increasing Cytoplasmic Localization of NRF2 in A549 Cells

2021

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We have identified triptolide as a novel NRF2 inhibitor, which significantly attenuates ARE-luciferase activity at nanomolar concentrations. Triptolide did not affect the level of NRF2, but significantly inhibited the expression of NRF2 target genes in A549 cells. We found that NRF2 possesses a previously unrecognized NES in the Neh2 domain, and that triptolide promotes an interaction between NRF2 and CRM1. Triptolide also decreased nuclear accumulation of NRF2, suggesting that it promotes nuclear export of NRF2. In addition, we show that triptolide decreased the expression of NRF2 target genes and increased intracellular oxidative stress, suppressing invasion and promoting cisplatin-induced apoptosis in A549 cells. Finally, oral administration of triptolide suppressed the growth of A549 xenografts in athymic mice by decreasing the expression of NRF2 target genes and promoting oxidative damages via the nuclear export of NRF2 and CRM1 in vivo. To the best of our knowledge, triptolide is the first type of compound to inhibit NRF2 by increasing cytoplasmic localization of NRF2.

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“…Importantly, from a screening of 644 natural compounds, Convallatoxin emerged as a novel and potent NRF2 inhibitor, presumably by promoting GSK-3 β / β -TrCP-dependent but KEAP1-independent proteolysis of NRF2. Notably, Convallatoxin sensitized A549 cells to 5FU-induced apoptosis, providing evidence that this natural compound might be a promising chemotherapeutic adjuvant in NSCLC treatment [300] (see Table 1).…”

Section: Therapeutic Strategies For Nrf2 Inhibition In Cancermentioning

confidence: 99%

Potential Applications of NRF2 Inhibitors in Cancer Therapy

Panieri¹,

Saso²

2019

Oxidative Medicine and Cellular Longevity

159

140

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The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis. Hence, in the last years, NRF2 has emerged as a promising target in cancer treatment and many efforts have been made to identify therapeutic strategies aimed at disrupting its prooncogenic role. By summarizing the results from past and recent studies, in this review, we provide an overview concerning the NRF2/KEAP1 pathway, its biological impact in solid and hematologic malignancies, and the molecular mechanisms causing NRF2 hyperactivation in cancer cells. Finally, we also describe some of the most promising therapeutic approaches that have been successfully employed to counteract NRF2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.

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Suppression of NRF2/ARE by convallatoxin sensitises A549 cells to 5-FU-mediated apoptosis

Cited by 25 publications

References 18 publications

RETRACTED: Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

RETRACTED: Exendin-4 prevented pancreatic beta cells from apoptosis in (Type I) diabetic mouse via keap1-Nrf2 signaling

Triptolide Downregulates the Expression of NRF2 Target Genes by Increasing Cytoplasmic Localization of NRF2 in A549 Cells

Potential Applications of NRF2 Inhibitors in Cancer Therapy

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