Raymond C. Bergan, MD Director, Experimental Therapeutics Robert H. Lurie Comprehensive Cancer Center Therapeutic modulation of adhesion and motility in human prostate cells Curricula: Cancer Biology Pharmacology and Toxicology E-mail:   r-bergan@northwestern.edu

Our laboratory is interested in understanding how human prostate cells regulate adhesion and motility, and the therapeutic modulation of that process. We investigate the basic biological processes underlying regulation of prostate cancer adhesion and motility, while searching for therapeutic agents which may modulate those processes. In the past, we have used a novel cell adhesion model to identify endoglin, a type 1 transmembrane TGFb protein, as an important regulator of adhesion and motility in human prostate cancer. We demonstrated that decreased endoglin expression led to cell detachment and increased invasion, and was seen in cancer compared to normal prostate. We used gene array methodology to identify endolgin.

We have demonstrated that R-Smad proteins are necessary for TGFb-mediated increases in cell adhesion, and that p38 MAP kinase phosphorylates Smad3. We went on to demonstrate that TGFb-mediated cell adhesion is regulated through a process involving signaling cross talk between Smad and MAP kinase signaling pathways, at the level of p38 MAP kinase (p38 MAP kinase phosphorylated Smad3).

In our work, we have linked the regulation of signaling with prior work related to genistein, a constituent of soy. Epidemiological studies associate soy consumption with a lower incidence of metastatic (not primary) prostate cancer (PCa). We have completed a series of experiments which directly support the hypothesis that genistein was inhibiting metastasis. We have shown that genistein increased PCa adhesion (thus antagonizing the first step in metastasis), and were the first to demonstrate that focal adhesion kinase (FAK) formed a molecular complex with b1-integrin, a transmembrane cell adhesion molecule. This complex formation is an initial event, preceding both cytoskeleton assembly and FAK phosphorylation.

Most recently, we have shown that genistein decreases both matrix metalloproteinase-2 (MMP-2) activity, as well as cell invasion, in human PCa. We have just completed a phase 1 pharmacokinetic study of genistein in men with PCa, demonstrating the effective (nM) concentrations of free genistein are readily attained with dietary amounts of genistein. We have initiated a phase 2 study in men about to undergo surgical removal of their prostates (to cure their PCa). The endpoints of this study are cell and molecular biomarkers, designed to determine whether genistein is exerting antimetastatic activity in humans.

Current interests in my lab relate to the ongoing characterization of the mechanism by which human PCa cells regulate invasion and motility. We seek to determine which of the four isotypes of p38 MAP kinase are important in above-described processes. In addition, we are seeking to characterize the molecular mechanism by which genistein exerts it’s effects upon MMP2. MMPs are regulated at a number of levels: transcription, translation, and pro-enzyme activation.

Publications:

Christopher H. Takimoto, Kira Glover, Xiaoke Huang, Steven A. Hayes, Lilia Gallot, Mary Quinn, Borko D. Jovanovic, Alla Shapiro, Leticia Hernandez, Andrew Goetz, Victor Llorens, Ronald Lieberman, James A. Crowell, Brett A. Poisson, Raymond C. Bergan. Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.  Cancer Epidemiology, Biomarkers and Prevention, 12, 1213-1221, 2003.

Steven A. Hayes, Xiaoke Huang, Suman Kambhampati, Leonidas C. Platanias, and Raymond C. Bergan. p38 MAP kinase modulates Smad dependent changes in human prostate cell adhesion. Oncogene 22, 4841-4850, 2003.

Yuequin Liu, Borko Jovanovic, Michael Pins, Chung Lee and Raymond C. Bergan. Over expression of endoglin in human prostate cancer suppresses cell detachment, migration and invasion. Oncogene, 21(54):8272-8281, 2002.

Yue-Qin Liu, Edward Kyle, Ronald Lieberman, James Crowell, Gary Kelloff, and Raymond Bergan. Focal adhesion kinase (FAK) phosphorylation is not required for FAK-ß-1-integrin complex formation. Clinical and Experimental Metastasis, 18(3):203-12, 2000.