Novel Nrf2/ARE activator, trans-Coniferylaldehyde, induces a HO-1-mediated defense mechanism through a dual p38α/MAPKAPK-2 and PK-N3 signaling pathway.
The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.|Department of Obstetrics and Gynecology, Taipei Medical University Hospital , Taipei 11031, Taiwan.
Huang-Hui
HH
Chen
Department of Pharmacy, Tajen University , Pingtung 90741, Taiwan.
Tai-Chi
TC
Wang
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Yen-Chen
YC
Lee
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Pei-Ting
PT
Shen
National Institute of Cancer Research, National Health Research Institutes , Tainan 70456, Taiwan.|Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University Medical College , Tainan 70101, Taiwan.
Jang-Yang
JY
Chang
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Teng-Kuang
TK
Yeh
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Chih-Hsiang
CH
Huang
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Hsin-Huei
HH
Chang
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Shu-Ying
SY
Cheng
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Chin-Yu
CY
Lin
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Chuan
C
Shih
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.
Chiung-Tong
CT
Chen
Department of Obstetrics and Gynecology, Taipei Medical University Hospital , Taipei 11031, Taiwan.|Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University , Taipei 11031, Taiwan.
Wei-Min
WM
Liu
Department of Obstetrics and Gynecology, Taipei Medical University Hospital , Taipei 11031, Taiwan.|Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University , Taipei 11031, Taiwan.
Ching-Hui
CH
Chen
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Zhunan 35053, Taiwan.|Institute of Clinical Pharmacy and Pharmaceutical Sciences, National Cheng Kung University Medical College , Tainan 70101, Taiwan.|Graduate Program for Aging, China Medical University , Taichung 40402, Taiwan.
Ching-Chuan
CC
Kuo
D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000099190:MAP-Kinase-Activated Kinase 2
D000171:Acrolein; D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C495636:Nfe2l2 protein, mouse; C075384:coniferaldehyde