Redox-sensitive transcription factors and their regulators as targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals
Authors: Young-Joon Surh
Journal: Cancer Research (2008)

SY08-01  The intracellular signal network as a prime target of chemopreventive phytochemicals. Over the past few decades, there has been a growing body of interest in identifying naturally occurring chemopreventive agents, particularly those present in our diet. Dietary chemopreventives are present predominantly in fruits, vegetables, grains, spices and herbs and have diverse chemical structures. Chemical substances derived from such plant-based diet are collectively called ‘phytochemicals’. Research directed toward elucidating molecular mechanisms underlying chemopreventive or chemoprotective actions of dietary phytochemicals has recognized components of signal transduction pathways as potential targets. Since the cellular signaling network often goes awry in carcinogenesis, it is fairly rational to target intracellular signaling cascades for achieving chemoprevention. Numerous molecules and events are involved in relaying intracellular signals. Both external and endogenous stimuli turn on or switch off critical events of this relay, thereby transmitting the appropriate signals to diverse downstream target molecules in a highly sophisticated fashion for the fine-tuning of cellular homeostasis. Components of upstream or cytoplasmic signaling networks include protein kinases, such as the family of proline-directed serine/threonine kinases named mitogen-activated protein (MAP) kinases, protein kinase C, phosphatidylinositol-3-kinase, protein kinase B/Akt, glycogen synthase kinase, etc. Chemopreventive phytochemicals can work as modifiers of signal transduction pathways to elicit their beneficial effects. Oxidative stress and inflammatory injuries are closely linked to each other in the process of multi-stage carcinogenesis. Thus, compounds with anti-inflammatory activities are anticipated to inhibit oxidative stress, and vice versa. We have investigated chemopreventive effects of some edible phytochemicals, with the focus on those with antioxidative and anti-inflammatory properties, and their underlying molecular mechanisms. Our research program has attempted to unravel common events mediated by two major redox-sensitive transcription factors, NF-κB and Nrf2, which mediate inflammatory and antioxidant signaling.  Nuclear factor kappa B (NF-κB). A growing body of data indicates that NF-κB, a ubiquitously expressed eukaryotic transcription factor, plays a central role in general inflammatory as well as immune responses. NF-κB is regarded as a potential link between inflammation and cancer.NF-κB, predominantly a heterodimer of p65 and p50 proteins, is normally sequestered in the cytoplasm as an inactive complex with the inhibitory protein, IκB. Upon stimulation with mitogens, pro-inflammatory cytokines, UV radiation, viral infection, bacterial toxins etc. it gets phosphorylated by activated IκB kinases (IKKs) or MAP kinases. Phosphorylated IκB, upon ubiquitination, is directed to proteasomes for degradation. The degradation of IκB allows NF-κB to translocate to the nucleus, and to bind to a -κB element located in the promoter regions of cox-2 and other proinflammatory genes, thereby controlling their expression. The transcriptional activation of NF-κB depends on the phosphorylation of its active subunit p65/RelA.The upstream IKK signalsome has been shown to phosphorylate both IκB and p65.  Nuclear factor erythroid 2 p45 (NF-E2)-related factor(Nrf2). The induction of phase II detoxifying or antioxidant enzymes represents one of the most important components of cellular defense mechanisms whereby a diverse array of electrophilic and oxidative toxicants can be eliminated from the cell before they damage genomic DNA.Some representative detoxifying/antioxidant enzymes include glutathione peroxidase, glutamate cysteine ligase, glutathione S-transferase, NAD(P)H:quinone oxidoreductase 1, and heme oxygenase-1. The induction of these enzymes is primarily regulated by Nrf2 as evidenced by negation of their expression in the genetically engineered Nrf2-deficient mice. Under normal physiological conditions, a cytoskeleton binding protein called Kelch-like erythorid CNC homologue (ECH)-associated protein 1 (Keap1) binds to Nrf2 thereby repressing its activation. Exposure to inducers of antioxidant/phase II detoxifying enzyme expression diminishes the affinity of Keap1 for Nrf2, which allows for the translocation of Nrf2 into the nucleus. Following nuclear translocation, Nrf2 binds to the specific consensus cis-element called the antioxidant-response elements (ARE) or the electrophile-responsive elements (EpRE) that are present in the promoter region of genes encoding many antioxidant enzymes. Therefore, Nrf2-Keap1 signaling has been recognized as an important target for chemoprevention and chemoprotection. While the molecular mechanisms involved in the Nrf2-deriven transcriptional activation of antioxidant enzymes are not fully understood, it has been hypothesized that covalent modification or oxidation of critical cysteine residues contained in Keap1 may facilitate the dissociation of the Keap1-Nrf2 complex or increase the stability of Nrf2. It has been suggested that cysteine residues present in Keap1 could serve as a molecular sensor for the recognition of the altered intracellular redox status triggered by electrophiles or reactive oxygen species (ROS).  Chemopreventive phytochemicals targeting NF-κB and Nrf2. Some naturally occurring cancer chemopreventive agents can suppress inappropriate overactivation of NF-κB signalling and/or activate Nrf2. Cysteine thiols, as presented in various transcription factors and their regulators, are recognized to function as redox sensors involved in the fine-tuning of transcriptional regulations of many genes essential for maintaining cellular homeostasis. Thus, oxidation or covalent modification of the thiol groups present in redox-sensitive transcription factors and their regulating molecules can provide a unique strategy for molecular target-based chemoprevention and cytoprotection that utilizes anti-inflammatory and antioxidant phytochemicals. Some examples of representative chemopreventive phytochemicals that modulate NF-κB and/or Nrf2 signaling will be presented.  Acknowledgments  Supported by the MOST/KOSEF through the National Research Laboratory (NRL) Program and the Innovative Drug Research Center for Metabolic and Inflammatory Diseases (R11-2007-107-00000-0).  References  1. Surh Y-J. Cancer chemoprevention with dietary phytochemicals.  Nature Reviews Cancer 2003;3:768-780.  2. Kundu J.K, Surh, Y-J. Breaking the relay in deregulated cellular signal transduction as a rationale for chemoprevention with anti-inflammatory phytochemicals. Mutat Res 2005;591:123-46.  3. Surh Y-J, Kundu JK, Na H-K, et al. Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J Nutr 2005;135 (12 Suppl):2993S-3001S.  4. Na H-K, Surh Y-J. Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotection. Mol Carcinog 2006;45:368-13.  5. Kim E-H, Surh Y-J. 15-deoxy-Δ12,14-prostaglandin j2 as a potential endogenous regulator of redox-sensitive transxcription factors. Biochem Pharmacol 2006;72: 1516-528.  6. Surh Y-J. More than spice: capsaicin in hot chili pepper makes cancer cells commit suicide. J Natl Cancer Inst 2002;94:1263-265.  7. Kim S-O, Kundu JK, Shin YK, et al. [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase. Oncogene 2005;24: 2558-567.  8. Lee J-S, Surh Y-J. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 2005;224:171-84.  9. Surh Y-J. Transcriptional regulation of cellular antioxidant defense mechanisms. In: Surh Y-J, Packer L, editors. Oxidative stress, inflammation, and health. Boca Raton: CRC/Taylor & Francis; p. 21-40.