Description of Research Expertise

RESEARCH INTERESTS

Biological effects of radiation, with emphasis on carcinogenesis and cancer prevention.

Key words: Cancer, proteases, protease inhibitors, prostate specific antigen (PSA), cancer prevention, oncogenes, space program, gene expression, ATR and Chk2, DNA repair.

DESCRIPTION OF RESEARCH

The research in this laboratory currently involves studies on the mechanism(s) involved in the induction of malignant transformation and its modification by various chemical agents in both in vitro and in vivo systems; radiation and chemicals are utilized as the carcinogenic agents in these studies. The modifying agents being studied include both promoting and suppressing agents for carcinogenesis, with emphasis on agents modifying free radical reactions and protease inhibitors. Studies on the mechanism of action of the protease inhibitor suppression of carcinogenesis have focused on the effects of these agents on the expression of specific oncogenes and proteases thought to be involved in the conversion of a cell to the malignant state. Human trials utilizing the soybean-derived protease inhibitor, the Bowman-Birk inhibitor(BBI), as a cancer chemopreventive agent are ongoing. Some of the current laboratory work involves studies on the effects of BBI on intermediate marker endpoints (IME) of carcinogenesis in human tissue. Examples of IME being studied include proteases, such as prostate specific antigen (PSA), expression of certain oncogenes, etc. A major new program in Space Radiation Biology has begun, with efforts being made to protect astonauts against the expected biologic effects of radiation encountered during space travel. This program focuses on the ability of selenium compounds to prevent and suppress the induction of cancer by radiation. For this work, it is hypothesized that selenium triggers expression and accumulation of ATR and Chk2 kinases that in turn regulate early signaling elements in checkpoint pathways, namely Rad9-Hus1-Rad1 (9-1-1), induced by ionizing radiation produced DNA damage.

ROTATION PROJECTS FOR 2004-2005

A study on the role of OXR1 in mechanisms underlying the cancer preventive role of SeM. In a search for human genes that function in protection against oxidative damage, an oxidation resistance gene, OXR1, has been discovered by Volker et. al. (PNAS, 2000, Vol. 97 no. 26). Using Gene Chip Microarray Technology (Affymetrix), we have identified OXR1 as one of the genes whose expression is regulated in prostate carcinoma (LNCaP) cells supplemented with L-Selenomethionine (SeM). As a part of a larger endeavor aimed at deciphering the mechanism(s) by which SeM plays a role as a protective agent against radiation-induced cancer, a specific project would be to examine the involvement of OXR1 in a SeM induced cascade(s). This project would involve use of quantitative PCR for monitoring of OXR1 transcriptional levels in human thyroid cells (HTori-3 cells), exposed to ionizing radiation in the presence or absence of selenomethionine (SeM). Further, the siRNA methodology would be used to prevent expression of OXR1 to investigate whether it is required for SeM protection of irradiated HTOri-3 cells against oxidative stress and transformation. Our belief is that OXR1 will be shown to play a role in the prevention of radiation induced DNA damage, whereby it will be a useful target in both cancer prevention and radiation therapy.

Generation of SeM database and data analysis using bioinformatics tools. In our efforts to explain the chemopreventive effects of SeM, various cell types are treated with this agent and gene expression data are collected. A specific project would involve generation of a database for the HTori-3 cell line (human thyroid) and its analysis for gene candidates that could be used either as biomarkers in cancer treatment or as targets in drug design.