Dietary phytochemicals and cancer prevention; Nrf2-mediated redox signaling; pharmacokinetics; pharmacodynamics
Our main research interest is in the areas of dietary phytochemicals and cancer prevention. The following specific research projects are currently being conducted in this laboratory:
1. Studies on dietary phytochemicals-mediated cellular signaling and cancer chemoprevention. Many dietary phytochemicals have been shown to possess health beneficial effects. My laboratory is utilizing the latest molecular, cellular, genomics, epigenetics and LC-MS to interrogate the biological responses elicited by these health promoting phytochemicals. Mammalian cells including human cells respond to our daily intake dietary phytochemicals by “non-classical receptor sensing” mechanism of electrophilic chemical-stress typified by ‘thiol modulated” induce cellular signaling events leading to gene expression of either pharmacologically beneficial effects, but some time also unwanted cytotoxicity. My laboratory is studying two major groups of dietary phytochemical cancer chemopreventive compounds (isothiocyanates and polyphenols), which are effective against chemical-induced as well as genetically induced animal carcinogenesis models. These compounds typically generate “cellular stress” and modulate gene expression of Phase II detoxifying/antioxidant enzymes GST, QR, HO-1 and GCS via the Keap1-Nrf2/ARE signaling pathway. However, using Nrf2 -/- mice coupled with Affymetrix microarray analyses, other category of genes including the Phase I drug metabolism enzyme cytochrome P450s, Phase III transporters, ubiquitination, electron transport, cell growth and apoptosis, cell adhesion, kinases, phosphotases and transcription factors modulated by these compounds appeared to be Nrf2-dependent, at least in normal tissues, leading to the overall cellular protective effects against oxidative stress or carcinogenic damages. Importantly, in tumor tissues, these phytochemicals appear to simultaneously modulate differentially over-expressed growth or inflammatory signaling molecules such as the MAPK, IKK/NF-kappa-B signaling pathways culminating the apoptotic or autophagic cell death of tumor or inflammatory cells. The differential signaling/gene expression between “normal” versus “abnormal” cells would dictate the varied biological responses and pharmacological effects in vivo elicited by these dietary compounds. The studies of these signaling pathways coupled with microarray or proteomic approaches may yield important insights into the potential beneficial health effects of naturally occurring dietary phytochemicals in human.
2. Nrf2-mediated redox signaling in anti-oxidative stress and anti-inflammatory. Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3-dependent substrate adaptor protein. Oxidative perturbation can impede Keap1-mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox-sensitive transcription factor. A new Nrf2-mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein may function as a redox-sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling. In addition, our lab recently found an internal ribosomal entry site (IRES) mediates redox-sensitive translation of Nrf2 in that translation of Nrf2 is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress. Furthermore, our lab found that the expression of Nrf2 is suppressed epigenetically by promoter methylation associated with methyl-CpG-binding protein 2 (MBD2) and histone modifications in the prostate tumor of TRAMP mice. Lastly, the Nrf2 knock-out mice have decreased anti-oxidative stress defence capacity with increased inflammatory signatures and Nrf2 plays a critical role in protecting against inflammation-associated colorectal cancer.
3. Pharmacokinetics, pharmacodynamics and personalized medicine. Many phenolic compounds/phytochemicals have poor in vivo bioavailability (systemic absorption) and may render them ineffective and/or required higher doses. We are trying to understand the absorption, metabolism and transport of xenobiotics in vivo resulting in appropriate blood and tissue levels leading to the pharmacodynamic response in appropriate tissues to elicit the biological effects. Differences between individuals (due to genetic polymorphism and or epigenetics) in drug metabolizing enzymes, transporters as well as target sites (receptors or enzymes or RNAs) would yield differential response to the same dose of xenobiotics in human.