Mortality of prostate cancer (PCa) patients is due to the emergence of androgen-independent (AI) PCa cells from the metastatic site. It is postulated that emergence of AI PCa cells derive from the stem cell population in prostate gland after malignant transformation. However, no effective regimens are currently available because the biology of AI PCa is not well characterized. We are currently characterizing the phenotype of the normal stem cell population and possible molecular defect(s) in those cells that can lead to the progression of prostate cancer, and in particular, the outgrowth of AI PCa cells.

Identification of DOC-2 cDNA reveals that it is a unique Src binding protein and represents a novel molecule in the homeostatic signal network of prostatic epithelium. We demonstrated that the DOC-2 gene is a potent growth inhibitor in human PCa and that the phosphorylation status of the N-terminal DOC-2 protein correlates with its inhibitory activity. To unveil the underlying mechanism associated with DOC-2 protein, we have identified a new member (i.e., DIP1/2) of GTPase-activating-protein that can interact with the N-terminal DOC-2 in prostatic epithelium. DIP1/2 also contains several unique motifs, such as the proline-rich domain, that can potentially interact with SH3-containing proteins involved in signaling cascades. In addition, we also showed that the C-terminal DOC-2 can interact with several effector proteins such as Grb2, Src, PI3K, and Nck. These data indicate that the DOC-2/DIP1/2 protein complex is a potential modulator for signaling cascades leading cell growth and differentiation.

Currently, we are planning to:

• Define each component of the DOC-2/DIP1/2 protein complex
• Examine the role of this complex in the regulation of homeostasis of prostate stem cells
• Establish a protein array to screen PCa specimens for possible defects of each component of this complex
• Develop agents, based on the biochemical properties of this complex, to alter the malignant phenotype of AI PCa cells

Principal Investigator:  Jer-Tsong Hsieh, Ph.D.

For more information about the Department of Urology, contact:

Phone: 214-648-4765, FAX: 214-648-4789

Mailing Address:  5323 Harry Hines Blvd., J8.148, Dallas, TX  75390-9110