Marc D. Basson, M.D., Ph.D.
Ping Dou, Ph.D.
Ahmad Heydari, Ph.D.
Ann G. Schwartz, Ph.D., M.P.H.

Dr. Basson's laboratory interests are in the effects of matrix proteins and physical forces such as strain and pressure on intestinal epithelial biology, as well as in the regulation of intestinal epithelial cell motility. In particular, one major project in laboratory is directed at examining the effect of pressure on cancer cell adhesion, based upon the hypothesis that the adhesion and metastasis of cancer cells shed from tumors or circulating within the lymphatics or vasculature may be activated by physical forces such as pressure, within the colonic lumen, the lymphatics or vasculature, or intraabdominal cavity or as created by surgical manipulation or laparoscopic insufflation. A second related area of investigation is directed at examining the effects of another physical force, repetitive deformation or strain, on intestinal epithelial biology, based upon the hypothesis that repetitive strain engendered by peristalsis, villous motility, or interactions with luminal contents may affect intestinal epithelial proliferation, differentiation, and motility. A third area of study focuses on the signals that regulate intestinal epithelial motility. Related work is characterizing the effects of extracellular pressure on macrophage phagocytosis. He is also a clinically active general and oncologic surgeon, and Chief of Surgery at the John D. Dingell VA Medical Center.
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Selected Publications

Zhang J, Li W, Sanders MA, Sumpio BE, Panja A, Basson MD. Regulation of the intestinal epithelial response to cyclic strain by extracellular matrix proteins. FASEB J. 17(8):926-928, 2003.

Sanders MA, Basson MD. Collagen IV regulates Caco-2 migration via a1b1 and a2b1 integrin-dependent Src kinase activation: evidence for ERK-dependent and ERK-independent mechanisms. Am J Physiol.  286(4):G547-G557, 2004.

Thamilselvan VJ, Basson MD. Pressure activates colon cancer cell adhesion by inside-out focal adhesion complex and actin cytoskeletal signaling.  Gastroenterology 126(1):8-18, 2004.

Shiratsuchi H, Basson MD. Extracellular pressure stimulates macrophage phagocytosis by inhibiting a pathway involving FAK and ERK.  Am J Physiol 286(6):C1358-66, 2004.

Shiratsuchi H, Basson MD. Activation of p38MAPKa by extracellular pressure stimulates macrophage phagocytosis. Am J Physiol. 288(5):C1083-93, 2005.

Sanders MA, Basson MD. p130cas but not paxillin is essential for CACO-2 intestinal epithelial cell spreading and migration on collagen IV. J Biol Chem, 280(25):23516-22, 2005.

Thamilselvan V, Basson MD. The role of the cytoskeleton in differentially regulating pressure-mediated effects on malignant colonocyte focal adhesion signaling and cell adhesion.  Carcinogenesis.  26(10):1687-97, 2005.

Basson MD, Sanders MA, Gomez R, Hatfield J, VanderHeide R, Thamilselvan V, Zhang  J, Walsh MF. Focal adhesion kinase protein levels in gut epithelial motility. Am J Physiol. 291(3):G491-9, 2006.

van der Voort van Zyp J. Conway WC, Craig DH, van der Voort van Zyp N., Thamilselvan V, Basson MD.  Extracellular pressure stimulates tumor cell adhesion in vitro by paxillin activation. Cancer Biology & Therapy. 5(9):1169-1178, 2006.

Zhang J, Owen CR, Sanders MA, Turner JR, Basson MD. The motogenic effects of cyclic mechanical strain on intestinal epithelial monolayer wound closure are matrix-dependent.  Gastroenterology. 131(4):1179-89, 2006.

Chaturvedi LS, Marsh HM, Shang X, Zheng Y, Basson MD.  Repetitive deformation activates FAK and ERK mitogenic signals in human Caco-2 intestinal epithelial cells through Src and Rac1. J Biol Chem. 282(1):14-28, 2007.

Chaturvedi LS, Marsh HM, Basson MD.  Src and Focal Adhesion Kinase mediate mechanical strain-induced proliferation and ERK1/2 phosphorylation in human H441 pulmonary epithelial cells.  Am J Physiol (Cell). 292(5):C1701-12, 2007.

Losanoff JE, Basson MD, Gruber SA, Huff H, Hsieh FH. Single wires versus double wire loops for median sternotomy closure. An experimental biomechanical study using a human cadaveric model.  Ann Thoracic Surg.  84(4):1288-93, 2007.

Basson MD. Effects of repetitive deformation on intestinal epithelial cells. Inflammopharmacology. 15(3): 109-114, 2007.

Shiratsuchi H, Basson MD. Akt2, but not Akt1 or Akt3 mediates pressure-stimulated serum-opsonized latex bead phagocytosis through activating mTOR and p70 S6 kinase. J Cell Biochem. 102(2):353-367, 2007.

Thamilselvan V, Craig DH, Basson MD. FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3K/Akt pathway. FASEB J. 21(8):1730-41, 2007.

Craig DH, Zhang J, Basson MD. Cytoskeletal signaling via α-actinin-1 mediates ERK 1/2 activation by repetitive deformation in human Caco-2 intestinal epithelial cells.  Am J Surg. 194(5):618-22, 2007.

Lin HS, Talwar HS, Tarca AL, Ionan A, Chatterjee M, Ye B, Wojciechowski J, Mohapatra S, Basson MD, Yoo GH, Peshek B, Lonardo F, Pan CJG, Draghici S, Abrams J, Tainsky MA. Proteomic approach for serum-based detection of head and neck cancer. Cancer Epidemiology, Biomarkers and Prevention.  In press, 2007.

Wang S, Basson MD. Identification of functional domains in AKT responsible for distinct roles of AKT isoforms in pressure-stimulated cancer cell adhesion through regulation of Focal Adhesion Kinase-Src interaction.  Am J Physiol (Cell). In press, 2007.

Sanders MA, Basson MD. Collagen IV regulates Caco-2 cell spreading and p130Cas phosphorylation by FAK-dependent and FAK-independent pathways. Biological Chemistry. In press, 2007.

Craig DH, Haimovich B, Basson MD.  α-Actinin-1 phosphorylation modulates pressure-induced colon cancer cell adhesion through regulation of Focal Adhesion Kinase-Src interaction.  Am J Physiol (Cell). In press, 2007.

Basson MD. An intracellular signal pathway that regulates cancer cell adhesion in response to extracellular forces .  Cancer Research.  In press, 2007.

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The main objective in this laboratory is aimed at discovering molecular targets of chemopreventive agents in pre-clinical studies, followed by validation in targeted cancer prevention clinical trials. Dr. Dou's laboratory is one of the first to report that proteasome inhibitors rapidly induce tumor cell apoptosis, selectively activate the cell death program in oncogene-transformed, but not normal or untransformed cells, and are able to trigger apoptotic death in human cancer cells that are resistant to various anticancer agents. Possible molecular mechanisms involve, at least in part, accumulation of the cyclin-dependent kinase inhibitor p27kip and the apoptosis inducer Bax. In addition, Dr. Dou and his colleagues have shown that proteasome inhibitors suppress human tumor growth in nude mice. Recently, Dr. Dou's laboratory has shown that some tea polyphenols and soy isoflavones potently and specifically inhibit the chymotrypsin-like activity of the proteasome in vitro and in vivo at physiological concentrations. Furthermore, his laboratory has established, for the first time, a computational molecular model that shows how tea polyphenols or soy isoflavones bind and target the proteasome beta5 subunit. This innovative computational model has been validated by comparison of predicted and actual activities of tea polyphenol analogs, either naturally occurring or rationally designed and synthesized. The future targeted prevention trials have been planned to examine whether polyphenols or isoflavones selectively inhibit proteasome activity in human cancer cells and whether such inhibitory activities correlate with clinical effects seen in serum and tissue samples as well as the potential involvement of genetic and environmental risk factors.

Selected Publications

Li, B., and Dou, Q.P. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc. Natl. Acad. Sci. USA, 97:3850-3855, 2000.

Nam, S., Smith, D.M., and Dou, Q.P. Inhibition of proteasome activity in vitro and in vivo by ester bond-containing tea polyphenols. J. Biol. Chem. 276:13322-13330, 2001.

Dou, Q.P., and Goldfarb, R.H., Bortezomib/ PS341 (millennium pharmaceuticals). IDrugs 5:828-834, 2002.

Smith, D.M., Wang, Z., Daniel, K.G., Guida, W.C., Chan, T-H, and Dou, Q.P. Mechanistic studies and model development of tea polyphenol proteasome inhibitors: Applications to rational drug design. Proteins: Structure, Function, and Genetics 23:58-70, 2004.

Daniel KG, Chen D, Orlu S, Cui QC, Miller FR, and Dou QP. Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells. Breast Cancer Res; 7:R897-R908, 2005.

Yang HJ, Chen D, Cui QC, Yuan X, and Dou QP. Celastrol, a triterpene extracted from the Chinese Thunder of God Vine, is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. (A figure was selected as the cover of the issue) Cancer Research 66, 4758-4765, May 1, 2006.

Kristin R. Landis-Piwowar, Vesna Milacic, Di Chen, Huanjie Yang, Yunfeng Zhao, Tak Hang Chan, Bing Yan, Q. Ping Dou. The Proteasome as a potential target for novel anticancer drugs and chemosensitizers. Drug Resist Updat, 2006; 9: 263-273, 2006.

Chen D, Cui QC, Yang HJ, and Dou QP. Disulfiram, A Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome Activity. Cancer Research 66, 10425-10433, 2006.

Milacic V, Chen D, Ronconi L, Landis-Piwowar KR, Fregona D, and Dou QP. A Novel Anticancer Gold(III) Dithiocarbamate Compound Inhibits the Activity of a Purified 20S Proteasome and 26S Proteasome in Human Breast Cancer Cell Cultures and Xenografts. Cancer Research 66, 10478-10486, 2006.

Chen D, Cui QC, Yang HJ, Barrea RA, Sarkar FH, Sheng S, Yan B, Reddy GPV and Dou QP. Clioquinol, a Therapeutic Agent for Alzheimer’s Disease, Has Proteasome-inhibitory, Androgen Receptor Suppressing, Apoptosis-inducing and Anti-tumor Activities in Human Prostate Cancer Cells and Xenografts. Cancer Res  67: 1636-1644, 2007

Yang HJ, Shi GQ and Dou QP. The Tumor Proteasome Is a Primary Target for the Natural Anticancer Compound Withaferin A Isolated from “Indian Winter Cherry”. Mol Pharmacol. Feb;71(2):426-37, 2007.

Landis-Piwowar KR, Huo CD, Chen D, Cui QC, Minic V, Shi GQ, Chan TH, and Dou QP. A Novel Pro-drug of the Green Tea Polyphenol (-)-Epigallocatechin-3-Gallate as a Potential Anti-Cancer Agent. Cancer Res 67: 4303-4310, 2007. 

Landis-Piwowar KR, Wan SB, Wiegand RA, Kuhn DJ, Chan TH, and Dou QP.
Methylation suppresses the proteasome-inhibitory function of green tea
polyphenols.J Cell Physiol. Oct;213(1):252-60, 2007.

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Ahmad Heydari, Ph.D.
Cancer Control and Prevention
Ph.D., Illinois State University, 1990

My research focuses on elucidating the molecular mechanism by which folate deficiency increases cancer risk. Folate deficiency is of important public health concern because of its role in the onset of many health problems, including birth defects, cardiovascular disease, Alzheimer's disease and cancer. A putative role for folate in protecting from cancer is convincingly suggested in both human and animal studies. My laboratory research findings suggest that the mechanism by which folate deficiency increases cancer risk is by reducing the ability to repair damaged DNA. We have developed a DNA repair deficient animal model that expresses a phenotype of cancer susceptibility and reduced DNA damage threshold. We propose that low levels of folate induce DNA repair deficiency by overwhelming the specific repair pathway, DNA polymerase β (β -pol) dependent Base Excision Repair pathway (BER). In support of our approach, we have demonstrated that aging and β -pol deficiency interact to accelerate the development of malignant lymphomas and adenocarcinoma and to increase tumor bearing load as well. We suggest that folate deficiency and β -pol haploinsufficiency (BER deficiency) will interact in a similar manner to accelerate tumor development in well-established models of liver and colon carcinogenesis. Our research aims to potentially identify the precipitating factors in the development of tumors and the impact that folate and BER deficiency have in these processes. These studies have important human health implications, as polymorphisms within the human population may render individuals haploinsufficient for β -pol, deficient in BER, and increase cancer risk by reducing their DNA damage tolerance. Use of the β -pol haploinsufficient mouse as a model of these human polymorphisms has the potential to demonstrate the impact of this gene/nutrient interaction and may identify an important variable in predicting individual susceptibility to cancer. Establishing that cancer risk is modifiable in an animal model with DNA repair deficiency, followed by development of a high throughput screening tool to identify individuals with reduced DNA repair capacity would allow caretakers to identify individuals at risk, and provide an intervention, i.e., folate supplementation. In addition to the above projects, my laboratory has been interested in dissecting the molecular mechanism of the anti-aging and anti-cancer effect of caloric restriction, and the potential role of DNA repair capacity in the beneficial effects of caloric restriction.  

Selected Publications

Cabelof D.C., Yanamadala S., Raffoul J.J., Soofi A.S., Guo Z. and A.R. Heydari (2003). Caloric restriction promotes genetic stability by induction of base excision repair and reversal of its age-related decline.   DNA Repair 2:295-307.

Cabelof D.C., Guo Z. , Raffoul J.J., Sobol, R.W., Wilson, S.H., Richardson A. and A.R. Heydari (2003). BER deficiency caused by β -pol haploinsufficiency: accelerated DNA damage and increased mutational response to carcinogens.   Cancer Research 63:5799-807 .

Raffoul J.J., Cabelof D.C., Nakamura J., Meira L.B., Friedberg E.C., and A.R. Heydari (2004). Apurinic/apyrimidinic endonuclease (APE/ref-1) haploinsufficient mice display tissue-specific differences in DNA polymerase β -dependent base excision repair. J. Biol. Chem. 279:18425-33.

Cabelof D.C., Raffoul J.J., Nakamura J., Kapoor D., Abdalla H., and A.R. Heydari (2004). Imbalanced base excision repair in response to folate deficiency is accelerated by β -pol haploinsufficiency . J. Biol. Chem 279:36504-13.

Cabelof, D.C., Raffoul, J.J., Ge, Y., Van Remmen, H., Matherly, L.H. and Heydari, A.R. (2006). Age-related loss of the DNA repair response following exposure to oxidative stress.   J Gerontology, A Biol Sci. Med. Sci. 61:427-434.

Cabelof, D.C., Ikeno, Y., Nyska, A., Busuttil, R.A., Anyanagwe, N., Vijg, J., Matherly, L.H., Tucker, J.D., Wilson, S.H., Richardson, A., and Heydari A.R. (2006) Haploinsufficiency in DNA polymerase β increases cancer risk with age and alters mortality rate.   Cancer Research 66:7460-7465.

Ann G. Schwartz, Ph.D., M.P.H.
Cancer Control
Ph.D., University of Michigan School of Public Health, 1986

Dr. Schwartz is studying the genetics underlying lung cancer risk. Dr. Schwartz' work focuses on familial risk of lung cancer, with a focus on early onset disease (< age 50). She recently reported differences in familial risk of lung cancer by race, with African Americans at double the risk associated with family history than whites. This was the first study to model lung cancer risk and provide risk estimates by age, race, family history and cigarette smoke exposure. Dr. Schwartz is also involved in several studies of candidate susceptibility genes, focusing on genes for enzymes involved in the metabolism of tobacco smoke carcinogens in early onset and non-smoking lung cancer and those involved in the metabolism of estrogen in a study of adenocarcinoma of the lung in women. The study of adenocarcinoma of the lung in women focuses on the contribution to risk of estrogens and includes the evaluation of ER-alpha and beta in lung tissue. Her recent work demonstrates ER-beta in lung cancer and differential survival associated with ER-beta expression in men. A new study is using admixture mapping in the search for susceptibility genes for lung cancer in African Americans.  

Selected Publications:

Cote ML, Kardia SLR, Wenzlaff AS, Ruckdeschel J, Schwartz AG.  Risk of lung cancer among Caucasian and African American relatives of individuals with early-onset lung cancer.  Journal of the American Medical Association 293: 3036-42, 2005.

Barnholtz-Sloan JS, Charkraborty R, Sellers TA, Schwartz AG.  Examining population stratification via individual ancestry estimates versus self-reported race.  Cancer, Epidemiology, Biomarkers and Prevention 14: 1545-51, 2005.

Schwartz AG, Prysak GM, Murphy V, Lonardo F, Pass H, Schwartz J, Brooks S.  Nuclear estrogen receptor β in lung cancer:  expression and survival differences by sex.  Clinical Cancer Research 11: 7280-7, 2005.

Simon MS, Korczak JF, Yee CL, Malone KF, Ursin G, Bernstein L, McDonald JA, Deapen D, Strom BL, Press MF, Marchbanks PA, Burkman RT, Weiss LK, Schwartz AG.  Breast cancer risk estimates for relatives of white and African American women with breast cancer in the Women’s Contraceptive and Reproductive Experiences Study.  J Clin Oncol 24: 2498-504, 2006.  

Cote ML, Wenzlaff AS, Bock CH, Land SJ, Santer SK, Schwartz DR, Schwartz AG.  Combinations of cytochrom P-450 genotypes and risk of early-onset lung cancer in Caucasians and African Americans: A population-based study.  Lung Cancer 55(3): 255-262, 2007.

Schwartz AG, Prysak GM, Bock CH, Cote ML.  The molecular epidemiology of lung cancer.  Carcinogenesis 28: 507-18, 2007.

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