Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK‑2 and PK-N3 Signaling Pathway

• Published in: Chemical research in toxicology 2015-09, Vol.28 (9), p.1681-1692
• Main Authors: Chen, Huang-Hui, Wang, Tai-Chi, Lee, Yen-Chen, Shen, Pei-Ting, Chang, Jang-Yang, Yeh, Teng-Kuang, Huang, Chih-Hsiang, Chang, Hsin-Huei, Cheng, Shu-Ying, Lin, Chin-Yu, Shih, Chuan, Chen, Chiung-Tong, Liu, Wei-Min, Chen, Ching-Hui, Kuo, Ching-Chuan
• Format: Article
• Language: English
• Subjects: Acrolein - analogs & derivatives; Acrolein - pharmacology; Animals; Heme Oxygenase-1 - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.5b00085

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.