Abstract
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.
Highlights
Coffee is one of the most popular and consumed beverages in the world
It is known that the ratio of nucleic/cytosolic nuclear factor E2-related factor 2 (Nrf2) is important for the phase II genes transcription
Coffee has been found to be cancer preventive for many cancer types. This phenomenon was attributed to the antioxidant scavenging properties of coffee polyphenols but can be attributed to Nrf2 induction by these compounds
Summary
A solid epidemiological data show that daily coffee consumption is associated with a decreasing risk for many types of cancers [1,2,3,4]. The risk for type II diabetes is decreased by daily coffee consumption [5]. Today about 8000 compounds are identified, most of them natural antioxidants [6,7] Besides their antioxidant activity, many polyphenols have other beneficial health properties such as antibacterial [8,9], anti inflammatory [10,11] and cancer preventive [12,13]. We showed in a previous work that coffee polyphenols act as antioxidants in the GI tract [14]
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