Uniform TitlePharmacogenomic and mechanistic studies on dietary factors in chemoprevention of cancer
NameNair, Sujit Sukumar (author), Kong, Ah-Ng Tony (chair), Minko, Tamara (internal member), You, Guofeng (internal member), Cai, Li (outside member), Rutgers University, Graduate School - New Brunswick,
DescriptionPharmacogenomic profiling of cancer has recently seen much activity with the accessibility of the newest generation of high-throughput platforms and technologies. A myriad of mechanistic studies have been devoted to identifying dietary factors that can help prevent cancer, with evidence gleaned from epidemiologic studies revealing an inverse correlation between the intake of cruciferous vegetables and the risk of certain types of cancer. To develop a comprehensive understanding of cancer pathogenesis, and potential for chemopreventive intervention with dietary factors, an integrated approach that encompasses both pharmacogenomic and mechanistic aspects is desirable. Our transcriptomic profiling of butylated hydroxyanisole-induced Nuclear Factor-E2-related factor 2 (Nrf2)-dependent genes in Nrf2-deficient mice identified several germane molecular targets for prevention. Toxicogenomic analyses of endoplasmic reticulum stress inducer tunicamycin in Nrf2-deficient mice elucidated Nrf2-regulated unfolded protein response effects. Mechanistic studies on a combination of sulforaphane and (-) epigallocatechin-3-gallate in HT-29 AP-1 (Activator Protein-1) cells revealed a synergy in colon cancer chemoprevention. Pharmacogenomic studies of this combination in PC-3 AP-1 cells provided a discursive framework for understanding putative crosstalk between Nrf2 and AP-1 in prostate cancer chemoprevention. Regulatory potential for concerted modulation of Nrf2 and Nuclear Factor-κB (Nfκb1) in inflammation and carcinogenesis was delineated by bioinformatic analyses. Metabolomic approaches identified potential prognostic biomarkers in human prostate cancer. Differential biological networks in prostate cancer were elicited in androgen-dependent 22Rv1 cells, androgen- and estrogen-dependent LNCaP cells and androgen-independent DU 145 and PC-3 cells. Taken together, our identification of Nrf2-regulated molecular targets by expression profiling using dietary factors, synergistic effects in combinatorial use of dietary factors in colon cancer, regulatory studies on crosstalk between Nrf2 and AP-1 in prostate cancer, bioinformatic analyses of concerted modulation of Nrf2 and Nfkb1 in inflammation and carcinogenesis, metabolomic identification of biomarkers, and delineation of target hubs in differential prostate cancer biological networks, greatly enhance our understanding of the transcriptional circuitry in cancer and important master regulatory nodes including Nrf2 that might potentially be exploited for chemopreventive intervention with dietary factors.
NoteIncludes bibliographical references (p. 311-331).
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.