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

Huang Hui Chen, Tai Chi Wang, Yen Chen Lee, Pei Ting Shen, Jang-Yang Chang, Teng Kuang Yeh, Chih Hsiang Huang, Hsin Huei Chang, Shu Ying Cheng, Chin Yu Lin, Chuan Shih, Chiung Tong Chen, Wei Min Liu, Ching Hui Chen, Ching Chuan Kuo

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21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1681-1692
Number of pages12
JournalChemical Research in Toxicology
Volume28
Issue number9
DOIs
Publication statusPublished - 2015 Aug 14

All Science Journal Classification (ASJC) codes

  • Toxicology

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    Chen, H. H., Wang, T. C., Lee, Y. C., Shen, P. T., Chang, J-Y., Yeh, T. K., Huang, C. H., Chang, H. H., Cheng, S. Y., Lin, C. Y., Shih, C., Chen, C. T., Liu, W. M., Chen, C. H., & Kuo, C. C. (2015). Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway. Chemical Research in Toxicology, 28(9), 1681-1692. https://doi.org/10.1021/acs.chemrestox.5b00085