The anticancer effects of resveratrol: modulation of transcription factors

Abstract

Resveratrol (3, 4', 5-trihydroxystilbene), a naturally occurring phytoalexin readily available in the diet, is reported to possess both chemopreventive and chemotherapeutic activities in several cancers. However, despite the identification of numerous molecular targets, the underlying mechanisms involved in the anticancer activities of resveratrol are not completely understood. Resveratrol is postulated to function as a potential signaling pathway modulator and, as such, is demonstrated to affect a multitude of signal transduction pathways associated with tumorigenesis and/or carcinogenesis; it is likely that this collective activity, rather than just a single effect, may play an important role in the anticancer properties of resveratrol. Since transcription factors control the expression of many genes, the elucidation of molecular targets of resveratrol involved in transcriptional regulation is necessary to better understand how this dietary phytochemical affects chemopreventive and chemotherapeutic processes. As a result, investigators have increasingly searched for and examined possible targets of resveratrol. In this review, we summarize the current knowledge on molecular targets, specifically transcription factors, that contribute to the observed anticancer effects of resveratrol related to 1) inhibition of carcinogenic activation and induction of carcinogen detoxification, 2) induction of growth arrest and apoptosis, and 3) suppression of proinflammatory signaling pathways related to cancer progression.

Fig. 1. Effects of resveratrol on AhR/Nrf2 signaling pathways

For a detailed description of AhR and Nrf2 signaling, refer to the text. Briefly, (A) PAH binds AhR (bound by the complex) and facilitates AhR translocation to the nucleus, where it forms a heterodimer with ARNT. The AhR/ARNT heterodimer then binds and trans-activates XRE-driven phase I/II enzyme promoters and initiates carcinogenesis (12). Resveratrol is demonstrated to inhibit AhR/ARNT recruitment to the promoter (red line; see text for references) and is speculated to displace PAH ligand binding and stabilize the cytosolic AhR complex (dotted green arrow; see text for reference). (B) Resveratrol-induced Nrf2 signaling confers protection against activated phase I enzymes (see text for references). Resveratrol promotes Nrf2 dissociation from Keap1 and nuclear translocation. In the nucleus, Nrf2 forms a heterodimer with small Maf proteins and trans-activates ARE-driven gene promoters (17).

Fig. 2. Effects of resveratrol on the FoxO signaling pathway

PI3K/Akt-mediated phosphorylation results in the inactivation of FoxO transcription factors. FoxO phosphorylation by PI3K/Akt facilitates FoxO interaction with 14-3-3 chaperone proteins and nuclear export; cytoplasmic sequestration inhibits FoxO-dependent transcription (38). Resveratrol blocks Akt activation and subsequent FoxO phosphorylation and nuclear export; on the other hand, resveratrol-induced FoxO expression facilitates trans-activation of anti-proliferative/pro-apoptotic forkhead response element (FHRE)-driven promoters (see text for references). GF, growth factor; RTK, receptor tyrosine kinase.

Fig. 3. Effects of resveratrol on the NF-κB signaling pathway

Activation by cytokine results in IKK phosphorylation of IκBα, resulting in IκBα degradation, and facilitation of NF-κB nuclear translocation and subsequent activation of transcription (49). Resveratrol is demonstrated it inhibit NF-κB signaling at all steps (see text for references).

Fig. 4. Schematic diagram of ATF3-mediated resveratrol action in colorectal cancer

Resveratrol increases the expression of both Egr-1 and KLF4, facilitating their interaction. The Egr-1/KLF4 complex binds to its response elements on the ATF3 promoter and mediates ATF3 trans-activation. Increased ATF3 expression results in increase of antitumor activity (58). Alternatively, resveratrol-increased Egr-1 or KLF4 expression results in trans-activation of antitumor-related target genes.