OF NFjBdriven Gene Induction By Phytoestrogens

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Several nutrients and non-nutritive phytochemicals are being evaluated in intervention trials for their potential as health benefiting compounds (28,179-181). Despite significant advances in our molecular understanding of various diseases, little is known about the mechanism of action of most phytochemicals (12,29,30,64,182). The chemopreventive effects that most dietary phytochemicals exert are likely to be the sum of several distinct mechanisms. A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to retain antioxidative and antiinflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Various studies demonstrate that flavonoids suppress NF-kB activation. As NF-kB is a transcription factor governing the expression of genes involved in the immune response, embryo or cell lineage development, cell apoptosis, cell cycle progression, inflammation, and oncogenesis, considerable attention has been paid to the upstream signaling pathways that lead to the activation of NF-kB. Many of these signaling molecules can serve as potential pharmaceutical targets for the specific inhibition of NF-kB activation leading to interruption of disease processes. Since many of the signal molecules in this pathway relay more than one of the upstream signals to downstream targets, it has been suggested that the transmission of signals involves a network, rather than a linear sequence in the activation of NF-kB. Thus, the detailed elucidation of the upstream signaling molecules involved in NF-kB activation and evaluation of their sensitivity to particular phytochemicals are currently a hot topic as this may allow the design of new chemoprotective drugs which selectively modulate NF-kB activity in various pathophysiological conditions. Disruption or deregulation of intracellular signaling cascades often leads to pathologies, and it is therefore important to identify these molecules in the signaling network that can be affected by individual chemopreventive phytochem-icals to allow for a better assessment of their underlying mechanisms (12,29,30,64,182).

In this respect, we and others are investigating in more detail how phytoestrogens can specifically modulate NF-kB driven gene expression (i.e., IL6, IL8, iNOS, COX2, ... ). Multiple lines of evidence indicate that IKK, PI3K, MAPK, and hormones are key elements of the intracellular-signaling cascades regulating NF-kB activity, and various levels of crosstalk have already been described (2,8,114,183,184). For example, breast cancers often progress from a hormone-dependent, nonmetastatic, anti-estrogen-sensitive phenotype to a hormone-independent, antiestrogen- and chemotherapy-resistant phenotype with highly invasive and metastatic growth properties (185-195). This progression is usually accompanied by transition from inducible to constitutive receptor tyrosine kinase (RTK)/MAPK signaling which affects ER function (becomes hormone ligand-independent), NF-kB regulation (high turnover of its inhibitor IkB results in constitutive NF-kB activity), or outgrowth of ER-negative cancer cells. The potential mechanisms for either intrinsic or acquired endocrine resistance are still poorly comprehended, but they clearly include ER-coregulatory proteins and crosstalk between the ER, NF-kB, growth factors, and kinase networks. Soy isoflavones are believed to contribute to the putative breast- and prostate-cancer-preventive activity of soy by abrogating NF-kB/DNA binding, as a consequence of reduced IkB phosphorylation, suppressed Akt activity, and inhibition of nuclear translocation of NF-kB. Besides some effects on DNA-binding, inhibition of the nuclear transactiva-tion capacity of NF-kB has been observed too, independent of IKK activity.

In the past few years, evidence has emerged that phytoestrogen binding hormone receptors, such as ER, AR, PR, AhR, PPAR, interact with NF-kB, and transcriptionally modulate each other (9-11,196-203). So far, the mode, according to which phytoestrogenic compounds mediate their estrogenic effects, has been studied in most detail. Assumptions range from mimicking normal estrogenic action to competitive inhibitory effects, which may block normal estrogenic action. Structural studies clearly reveal changes in ER-conformation upon binding of classic estrogens as compared to phytoestro-gens, which may already suggest ligand selective (cofactor) dependent activities (48,49,52,196,204-211). Interestingly, phytoestrogens seem to preferentially mediate their effects via ER^, whereas classical estrogen acts via both receptors ERa and ER^ (212,213). As such, phytoestrogens may act as natural SERMs that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ER^ that trigger transcriptional pathways (53-55,212,214). Interestingly, ER^ was found to be more potent in NF-kB transrepression than ERa and may suggest distinct modulatory effects of synthetic estrogens vs. phytochemicals at the level of NF-kB gene regulation. As crosstalk of phytoestrogens with PPAR, AhR, PR, vitamin D, ERR responses has been reported as well, the complexity of their hormone activities is further augmented (9,64,196-200,215-217). At another level, involvement of tyrosine phosphorylation (218,219) in TNF (101,220-222), Toll like receptors (TLR) (223) and growth factor signaling (EGF, her/neu) (32,33,224-229) has been demonstrated at the receptor level, which may be sensible to inhibition by phytoestrogens (62,230,231), and decrease further downstream-signaling cascades such as Akt, IKK, and MAPK signaling pathways (29,33,182,184,232-234).

Finally, it has been postulated that reactive oxygen species (ROS) may act as second messengers leading to NF-kB activation, whereas antioxidants may block this activity (235). Whether this mechanism holds through, has recently become a matter of hot debate, since antioxidants were found to lower ligand-receptor affinity (i.e., TNF/TNFR) and in this way, lower the magnitude of receptor signaling (236-238).

Considering the pleiotropic activities of flavonoids, i.e., as hormone ligands (i.e., ER, Ar, AhR, PPAR, ESR, ...), tyr-osine kinase inhibitors, or antioxidants, it will be interesting to evaluate what activity predominates in its NF-kB modula-tory activities in a gene- or cell-specific context, as compared to effects of classical estrogens (12,29,64). Further structure function analysis of phytochemicals may allow to define core structure elements, which are responsible to fulfill part of their subactivities.

In many cases, the chemopreventive effects of dietary chemopreventives in cultured cells or tissues are only achievable at supraphysiological concentrations (such concentrations might not be attained when the phytochemicals are administered as part of diet) since metabolization and/or chaperone protection of these compounds may be less efficient in tissue culture setups (12,27,56,239). As phenolic phyto-chemicals are often present as glycosides or are converted to other conjugated forms after absorption, it would be of high interest to compare relative activities of each metabolite in modulation of NF-kB activity. Both pharmacokinetic properties and bioavailability are key problems in investigating the dietary prevention of cancer and should be assessed carefully before undertaking intervention trials with dietary supplements. The development and use of chemopreventive agents for intervention trials involve many scientific disci plines. With the advances in techniques to assess single nucleotide polymorphisms (SNPs), we are now more aware of the specific genes that can directly and indirectly contribute to individual differences in the susceptibility to carcinogenesis and/or drug metabolization pathways (240). When high-risk groups are identified, practitioners might be able to recommend specific dietary supplements that can modulate or restore the cellular signaling events which are likely to be disrupted in these individuals. The term "nutrage-nomics'' has been coined, and much attention is being focused on this relatively new area of research (28,240). Tailored supplementation with designer foods that consist of chemo-preventive phytochemicals—each having their own distinct anticancer mechanisms—will be available in the near future. These should be developed in line with advances in the genetic and molecular epidemiology ofcarcinogenesis.

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