Enhanced 4-Hydroxynonenal Resistance in KEAP1 Silenced Human Colon Cancer Cells

被引：20

作者：

Jung, Kyeong-Ah ^{[1
]}

Kwak, Mi-Kyoung ^{[1
]}

机构：

[1] Catholic Univ Korea, Coll Pharm, Gyeonggi Do 420743, Bucheon, South Korea

来源：

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY | 2013年 / 2013卷

基金：

新加坡国家研究基金会;

关键词：

ALDO-KETO REDUCTASES; ANTIOXIDANT RESPONSE; OXIDATIVE STRESS; GENE-EXPRESSION; LIPID-PEROXIDATION; ADAPTIVE RESPONSE; BETA-CATENIN; NRF2; IDENTIFICATION; ACTIVATION;

D O I：

10.1155/2013/423965

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Nuclear factor erythroid 2-related factor 2 (NRF2) is the transcription factor that regulates an array of antioxidant/detoxifying genes for cellular defense. The conformational changes of Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor protein of NRF2, by various stimuli result in NRF2 liberation and accumulation in the nucleus. In the present study, we aimed to investigate the effect of KEAP1 knockdown on NRF2 target gene expression and its toxicological implication using human colon cancer cells. The stable KEAP1-knockdown HT29 cells exhibit elevated levels of NRF2 and its target gene expressions. In particular, the mRNA levels of aldo-keto reductases (AKR1C1, 1C2, 1C3, 1B1, and 1B10) were substantially increased in KEAP1 silenced HT29 cells. These differential AKRs expressions appear to contribute to protection against oxidative stress. The KEAP1-knockdown cells were relatively more resistant to hydrogen peroxide (H2O2) and 4-hydroxynonenal (4HNE) compared to the control cells. Accordantly, we observed accumulation of 4HNE protein adducts in H2O2- or 4HNE-treated control cells, whereas KEAP1-knockdown cells did not increase adduct formation. The treatment of KEAP1-silenced cells with AKR1C inhibitor flufenamic acid increased 4HNE-induced cellular toxicity and protein adduct formation. Taken together, these results indicate that AKRs, which are NRF2-dependent highly inducible gene clusters, play a role in NRF2-mediated cytoprotection against lipid peroxide toxicity.

引用

页数：16

共 65 条

[1] Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles [J].

Agyeman, Abena S. ;

Chaerkady, Raghothama ;

Shaw, Patrick G. ;

Davidson, Nancy E. ;

Visvanathan, Kala ;

Pandey, Akhilesh ;

Kensler, Thomas W. .

BREAST CANCER RESEARCH AND TREATMENT, 2012, 132 (01) :175-187

[2]

Bonnesen C, 2001, CANCER RES, V61, P6120

[3] The reactive oxygen species- and Michael acceptor-inducible human aldo-keto reductase AKR1C1 reduces the α,β-unsaturated aldehyde 4-hydroacy-2-nonenal to 1,4-dihydroxy-2-nonene [J].

Burczynski, ME ;

Sridhar, GR ;

Palackal, NT ;

Penning, TM .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (04) :2890-2897

[4] Roles of 3-nitrotyrosine- and 4-hydroxynonenal-modified brain proteins in the progression and pathogenesis of Alzheimer's disease [J].

Butterfield, D. Allan ;

Reed, Tanea ;

Sultana, Rukhsana .

FREE RADICAL RESEARCH, 2011, 45 (01) :59-72

[5] Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): Role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs [J].

Byrns, Michael C. ;

Penning, Trevor M. .

CHEMICO-BIOLOGICAL INTERACTIONS, 2009, 178 (1-3) :221-227

[6] Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype [J].

Devling, TWP ;

Lindsay, CD ;

McLellan, LI ;

McMahon, M ;

Hayes, JD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (20) :7280-7285

[7] Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants [J].

Dinkova-Kostova, AT ;

Holtzclaw, WD ;

Cole, RN ;

Itoh, K ;

Wakabayashi, N ;

Katoh, Y ;

Yamamoto, M ;

Talalay, P .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (18) :11908-11913

[8] Identification of the highly reactive cysteine 151 in the chemopreventive agent-sensor Keap1 protein is method-dependent [J].

Eggler, Aimee L. ;

Luo, Yan ;

van Breemen, Richard B. ;

Mesecar, Andrew D. .

CHEMICAL RESEARCH IN TOXICOLOGY, 2007, 20 (12) :1878-1884

[9] Modifying specific cysteines of the electrophile-sensing human Keap1 disrupt binding to the protein is insufficient to Nrf2 domain Neh2 [J].

Eggler, AL ;

Liu, GW ;

Pezzuto, JM ;

van Breemen, RB ;

Mesecar, AD .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (29) :10070-10075

[10] CHEMISTRY AND BIOCHEMISTRY OF 4-HYDROXYNONENAL, MALONALDEHYDE AND RELATED ALDEHYDES [J].

ESTERBAUER, H ;

SCHAUR, RJ ;

ZOLLNER, H .

FREE RADICAL BIOLOGY AND MEDICINE, 1991, 11 (01) :81-128

← 1 2 3 4 5 6 7 →