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

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

doi:10.1080/10715762.2018.1489132

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

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

Department of Pharmacy

Dongguk University

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.

Original language	English
Pages (from-to)	1416-1423
Number of pages	8
Journal	Free Radical Research
Volume	52
Issue number	11-12
DOIs	https://doi.org/10.1080/10715762.2018.1489132
State	Published - 2 Dec 2018

Keywords

5-Fluorouracil (5-FU)
antioxidant response element (ARE)
convallatoxin
NRF2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/10715762.2018.1489132

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

abstract = "NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.",

keywords = "5-Fluorouracil (5-FU), antioxidant response element (ARE), convallatoxin, NRF2",

author = "June Lee and Kang, {Jong Su} and Nam, {Le Ba} and Yoo, {Ok Kyung} and Keum, {Young Sam}",

note = "Publisher Copyright: {\textcopyright} 2018, {\textcopyright} 2018 Informa UK Limited, trading as Taylor & Francis Group.",

year = "2018",

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doi = "10.1080/10715762.2018.1489132",

language = "English",

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journal = "Free Radical Research",

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TY - JOUR

T1 - Suppression of NRF2/ARE by convallatoxin sensitises A549 cells to 5-FU-mediated apoptosis

AU - Lee, June

AU - Kang, Jong Su

AU - Nam, Le Ba

AU - Yoo, Ok Kyung

AU - Keum, Young Sam

PY - 2018/12/2

Y1 - 2018/12/2

N2 - NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.

AB - NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3β and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.

KW - 5-Fluorouracil (5-FU)

KW - antioxidant response element (ARE)

KW - convallatoxin

KW - NRF2

UR - http://www.scopus.com/inward/record.url?scp=85053306631&partnerID=8YFLogxK

U2 - 10.1080/10715762.2018.1489132

DO - 10.1080/10715762.2018.1489132

M3 - Article

C2 - 29902094

AN - SCOPUS:85053306631

SN - 1071-5762

VL - 52

SP - 1416

EP - 1423

JO - Free Radical Research

JF - Free Radical Research

IS - 11-12

ER -

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

Abstract

Keywords

UN SDGs

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