The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines

• Published in: Redox biology Vol. 4; no. C; pp. 48 - 59
• Main Authors: Sirota, R., Gibson, D., Kohen, R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01.04.2015
• Subjects: Antioxidants - chemistry; Antioxidants - metabolism; Caffeic acid; Caffeic Acids - chemistry; Caffeic Acids - metabolism; Catechols - metabolism; Cell Line, Tumor; Cisplatin; Coffee; Coffee - chemistry; Female; Humans; Hydrogen Peroxide - pharmacology; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2 - biosynthesis; NF-E2-Related Factor 2 - metabolism; Nrf2; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Oxidative Stress - drug effects; Polyphenols; Polyphenols - chemistry; Polyphenols - metabolism; Research Paper; Signal Transduction - drug effects; Polyphenols; Coffee; Nrf2; Caffeic acid; Cisplatin
• DOI: 10.1016/j.redox.2014.11.012
• ISSN: 2213-2317

In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world. It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2/Keap1 pathway as well as their direct antioxidant activity. However, activation of Nrf2 in cancer cells might lead to resistance towards therapy through induction of phase II enzymes. In the present work we hypothesize that caffeic acid (CA), a coffee polyphenol, might act as an electrophile in addition to its nucleophilic properties and is capable of inducing the Nrf2/EpRE pathway in cancer cells. The results indicate that CA induces Nrf2 translocation into the nucleus and consequently its transcription. It has been demonstrated that generated hydrogen peroxide is involved in the induction process. It has also been found that this process is induced predominantly via the double bond in CA (Michael acceptor). However, surprisingly the presence of both nucleophilic and electrophilic moieties in CA resulted in a synergetic activation of Nrf2 and phase II enzymes. We also found that CA possesses a dual activity, although inducing GSTP1 and GSR, it inhibiting their enzymatic activity. In conclusion, the mechanism of induction of Nrf2 pathway and phase II enzymes by CA has been elucidated. The electrophilic moiety in CA is essential for the oxidation of the Keap1 protein. It should be noted that while the nucleophilic moiety (the catechol/quinone moiety) can provide scavenging ability, it cannot contribute directly to Nrf2 induction. It was found that this process may be induced by H2O2 produced by the catechol group. On the whole, it appears that CA might play a major role in the cancer cells by enhancing their resistance to treatment.