Pharmacogenomics and toxicogenomics of cancer chemopreventive compounds, MAP Kinases / Nrf2 transcription factor-mediated gene expression, and pharmacokinetics and pharmacodynamics of drug action.

Many naturally occurring cancer chemopreventive compounds can modulate signal transduction events leading to gene expression and prevention of cancer. The research of my laboratory is to study two important cellular signaling pathways, the mitogen-activated protein kinases (MAPKs) and the caspases pathways activated by these compounds as well as environmental agents and chemotherapeutic drugs. One of the downstream targets that are modulated by chemopreventive agents-induced MAPK signaling is the bZIP transcription factors Nrf2/Maf which induce cellular defensive enzymes via the antioxidant response element (ARE). Our lab had shown that various MAPK proteins modulate the transcriptional activity of Nrf2 on ARE-luciferase reporter gene leading gene to expression of cellular defense enzymes such as heme-oxygenase-1 and Phase II drug metabolizing enzymes. Our approach to investigate various chemopreventive agents is to combine biochemistry and molecular biology in cell cultures combined with appropriate in vivo animal animal models for human cancers of colon and prostate. Ongoing projects focus on: (i) Chemoprevention of cancer: Preclinical and clinical studies of chemopreventive agents; (ii) Drug metabolism: Biochemistry, pharmacology and regulation of gene expression of drug metabolizing enzymes (cytochrome P450s and phase II enzymes) in relationship to carcinogenesis and chemoprevention; (iii) Cellular signal transduction: MAPK; ERK, JNK, p38 in regulation of gene expression in cell survival and apoptosis; (iv) Apoptosis: Role of caspases, TRAIL and death receptors (DRs) in apoptosis; (v) Pharmacogenomics and toxicogenomics; (vi) Pharmacokinetics, and pharmacodynamics of anti-cancer drugs (preventive and chemotherapeutics) and environmental agents; and (vii) Prostate cancer: Biology, signaling, prevention and therapy.

	Jeong, W.-S., Keum, Y.-S., Chen, C., Jain, M.R., Shen, G., Li, W., Kim, J.-H., and Kong, A.-N.T . Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. J. Biochem. Mol. Biol. 38: 167-176, March 31, 2005.
	Hebbar, V., Shen, G., Hu, R., Kim, B.-R., Chen, C., Korytko, P.J., Crowell, J.A., Levine, B.F. and Kong, A.-N.T . Toxicogenomics and cDNA Microarray analysis of gene expression profiles elicited by resveratrol in rat liver. Life Sciences 76: 2299-2314, April 2005 (Available online January 29, 2005).
	Xu, C.-J., Shen, G., Chen, C., Genlinas, C., and Kong, A.-N.T . Suppression of NF- k B and NF- k B-regulated Gene Expression by sulforaphane and PEITC through I k B a , IKK pathway in human Prostate PC-3 cells. Oncogene 24:4486-4495, June 2005 (Available online March 18, 2005).
	Chen, C. and Kong, A.-N.T . Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects (Invited Review). Trends in Pharmacol. Sci. June; 26(6):318-326, 2005 (Available online 6 May 2005).