Mortality of prostate cancer (PCa) patients is due to the emergence of androgen-independent (AI) PCa cells from 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 normal stem cell population and possible molecular defect(s) in those cells that can lead to prostate cancer progression, in particular, the outgrowth of AI PCa cells.
Identification of DOC-2/DAB2 cDNA reveals that it is a unique Src binding protein and represents a novel molecule in the homeostatic signal network of prostatic epithelium. We demonstrate that the DOC-2/DAB2 gene is a potent growth inhibitor in human PCa and the phosphorylation status of the N-terminal DOC-2/DAB2 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 or DAB2IP) 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 proline-rich domain that can potentially interact with SH3-containing proteins involved in signaling cascades. We also show that the C-terminal DOC-2/DAB2 can also 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. In addition, we also found that epigeentic regulation such as DNA hypomethylation and histone modification plays a critical role in modulating the expression of these genes in prostate cancer. Currently, we are planning to (1) define each component of DOC-2/DIP1/2 protein complex. (2) Examine the role of this complex in the regulation of homeostasis of prostate stem cell. (3) Establish a protein array to screen PCa specimens for any possible defects of each component of this complex. (4) Develop small molecules, based on the biochemical properties of this complex, to alter the malignant phenotype of AI PCa cells. (5) Combine molecular and cellular imaging tools to monitor the efficacy of small molecule therapy on prostate cancer using xenograft model.
On the other hand, we are exploring the potential application of gene therapy on both PCa and transitional carcinoma (TCC) of bladder. We are working on the improvement of the viral uptake of recombinant adenoviral vector. We found the decreased or absent coxsackie and adenoviral receptor (CAR), a rate-limiting step of viral uptake, is often found with cancer lines and correlates with disease progression. Biologically, a little is known about the role of CAR in PCa and TCC progression. We recently demonstrate that CAR has a negative impact on the growth of both cancer types. Based on these findings, we decide to (1) develop a screening/ monitoring method for determining the status of CAR in cancer patients before and during gene therapy trial. (2) Study the structural functional relationship of CAR molecule and its down stream signal cascade. (3) Delineate the regulation of CAR gene. (4) Establish a high throughput screening system for agent(s) with inducing endogenous CAR gene expression activity. (5) Develop imaging tool to detect CAR expression of tumor mass using pre-clinical model.
RESEARCH INTERESTS
Signal network defects in prostate cancer
Prostate stem cell
Small molecular therapy
Bladder cancer gene therapy
RECENT PUBLICATIONS
Zhou, J., Hernandez, G., Tu, S., Huang, C.L., Tseng, C.P., and Hsieh, J.T., "The mechanism of antiandrogen effect of DOC-2/DAB2 on androgen receptor-mediated cell growth in androgen independent prostate cancer" Cancer Res., 65:9906-9913, 2005
Chen, H, Karam. J.A., Schultz, R., Zhang, Z., Ducan, C., and Hsieh, J.T., "Cloning of mDAB2IP gene, a novel member of the RasGTPase-activating protein family and characterization of its regulatory region" DNA and Cell Biol., 25:232-245, 2006
Okegawa, T., Sayne, J.R., Nutahara, K., Pong, R.C., Saboorian, H., Kabbani, W., Higashihara, E., and Hsieh, J.T., "A histone deacetylase inhibitor enhances adenoviral infection of renal cancer cells" J. Urol., 177:1163-1168, 2007
Karam, J.A., Fan, J., Stanfield, J., Richer, E., Benaim, E.A., Frenkel, E.P., Sagalowsky, A.I., Antich, P.P., Mason, R.P., and Hsieh, J.T., "The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-Azacytidine in human bladder cancer therapy" Int. J. Cancer, 120:1795-1802, 2007
Zhang, Z., Stanfield, J., Frenkel, E.P., and Hsieh, J.T., "Histone deacetylase inhibitor (FK228) enhances the therapeutic efficacy of docetaxel in androgen independent prostate cancer" Urol., In press, 2007
SIGNIFICANT PUBLICATIONS
Chen H, Tu SW, Hsieh JT, "Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer" JBC, 280:22437-22444, June 2005
Zhou, J., Fan, J., and Hsieh, J.T., "Inhibition of mitogens-elicited signal transduction and growth in prostate cancer with a small peptide derived from the functional domain of DOC-2/DAB2 delivered by a unique vehicle" Cancer Res., 66:8822-8828, 2006
Zhang, Z., Karam, J., Frenkel, E.P., Sagalowsky, A., and Hsieh, J.T., "The Potential Application of Epigenetic Modifiers in the Treatment of Prostate and Bladder Cancer" Urologic Oncol., 24:152-160, 2006
Pong, R.C., Roark, R., Ou, J., Fan, J., Stanfield, J., Frenkel, E., Sagalowsky, A., and Hsieh, J.T., "Mechanism of increased coxsackie and adenovirus receptor gene expression and adenovirus uptake by phytoestrogen and histone deacetykase inhibitor in human bladder cancer cells and the potential clinical application" Cancer Res., 66:8822-8828, 2006
Karam, J. A., Shariat, S.F., Huang, H-Y., Ashfaq, R., Shapiro, E., Lotan, Y., Sagalowsky, A.I., and Hsieh, J.T., "Decreased DOC-2/DAB2 expression in urothelial carcinoma of the bladder" Clin. Cancer Res., 13:4400-4406, 2007
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