Harris Bernstein

Professor of Cell Biology and Anatomy

Mail: Arizona Health Sciences Center 6112
P.O. Box 245044
Tucson AZ 85724-5044
Phone: 520/626-6069
Fax: 520/626-2097
e-mail: bernstein3@earthlink.net

Summary of Research Activities

At least 90 percent of colorectal cancer deaths can be attributed to lifestyle factors, including diet and smoking, and are potentially preventable. A high-fat diet is a likely major cause of colon cancer. Bile acids are produced by the body to aid in digestion of fats and are known to be promoters of colon cancer. Cells that are excessively damaged by bile acids undergo a controlled process of cell death referred to as apoptosis. This process is beneficial to the body because it removes cells with unrepaired DNA damages; such damaged cells, when allowed to survive, tend to mutate and give rise to cancer. While we and others have found that colonic cancer cells are defective in apoptosis, we also found that the normal-appearing, flat colonic tissue of individuals in high-risk groups is deficient in its ability to undergo apoptosis as well. This appears to be a precancerous change in these high-risk individuals.

We have found that bile acid treatment of cells induces changes in the levels of proteins involved in the cellís response to stress. These protein changes may reflect an effort by the cell to protect itself against damages that otherwise would cause apoptosis, or they may be part of the pathway of apoptosis itself. The apoptosis-resistant cells that are found in normal-appearing colonic tissue of high-risk individuals would be expected to differ from apoptosis-competent cells in the expression of these stress proteins. Since the expression of these specific proteins can be measured accurately and specifically using an automated staining system and computerized imaging program in routinely prepared biopsy specimens, we hypothesize that they should prove useful as biomarkers for colon cancer risk.

We have chosen seven specific genes that we expect may have an altered level of expression in cells resistant to apoptosis. We have shown that each of these gene products is induced by bile acids. The seven gene products to be examined are GRP78 and Hsp70 (chaperone proteins responsive to protein unfolding); NFkB and c-fos (responsive to oxidative stress); GADD153 and PARP (responsive to DNA damage); and iNOS (elevated in colon cancers). A major goal of our research is to test the feasibility of using altered patterns of expression of these genes as a practical biomarker for assessing colon cancer risk. We also expect our research to significantly increase our understanding of the early stages of colon carcinogenesis before gross lesions are detectable.

Selected Publications

* Bernstein C, Bernstein H, Garewal H, Dinning P, Jabi R, Sampliner RE, McCuskey MK, Panda M, Roe D, LíHeureux L, Payne CM. A bile acid-induced apoptosis assay for colon cancer risk, and associated quality control studies. Cancer Res 59:2353-2357, 1999.

* Washo-Stultz D, Hoglen N, Bernstein H, Bernstein C, Payne CM. Role of nitric oxide and peroxynitrite in bile salt-induced apoptosis: relevance to colon carcinogenesis. Nutrition and Cancer 35:193-202, 1999.

* Crowley CL, Payne CM, Bernstein H, Bernstein C, Roe D. The NAD* precursors, incotinic acid and nicotinamide protect cells against deoxycholate induced apoptosis, increase levels of glyceraldehyde-3-phosphate dehydro-genase and decrease constitutive levels of activated NF-kB and GRP78. Cell Death Diff. 7:314-326, 2000.

*Bernstein, Carol, Harris Bernstein, Claire M. Payne and Harinder Garewal. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutation Research Reviews 511:145-178 (2002).

*Bernstein, Harris, Claire M. Payne, Kathleen Kunke, Cara L. Crowley-Weber, Caroline N. Waltmire, Katerina Dvorakova, Hana Holubec, Carol Bernstein, Richard R. Vaillanvourt, Deborah A. Raynes, Vincent Guerriero and Harinder Garewal. A proteomic study of resistance to deoxycholate-induced apoptosis, plus Online Supplemenatry Material at http://www.carcin.oupjournals.org Carcinogenesis 25:681-692 (2004).

*Bernstein, Harris, Carol Bernstein, Claire M. Payne and Harinder Garewal. Bile acids as carcinogens in human gastrointestinal cancers. Reviews in Mutation Research in press 9/06/04

Collaborative Research

* Claire Payne, Ph.D., Cell Biology and Anatomy: Mechanisms of apoptosis
* Carol Bernstein, Ph.D., Cell Biology and Anatomy: Resistance to bile acid induced apoptosis
* Harinder Garewal, M.D., Ph.D., Medicine: Gastrointestinal Cancer
* Katerina Dvorakova, Ph.D., Cell Biology and Anatomy: Barretts Esophagus
* Richard Sampliner, M.D., VA Medical Center: Gastrointestinal Cancer