department of pharmacology

David Danielpour, Ph.D.

danielpour

Professor of General Medical Sciences/Oncology and Pharmacology

Ireland Cancer Center

School of Medicine
Case Western Reserve University

Wolstein Research Building, Room 3532
2103 Cornell Road
Cleveland, Ohio 44106

Phone: (216) 368-5670
Fax: (216) 368-8919
E-mail: dxd49@case.edu

Research

My laboratory focuses on the role of transforming growth factor-beta (TGF-ß) as a tumor suppressor and regulator of growth, apoptosis and androgenic responses in the prostate. TGF-ßs are a family of 25 kDa dimeric regulatory peptides that function as autocrine, paracrine and possibly endocrine regulators of growth, apoptosis and differentiation in numerous tissues. Signal transduction by these peptides is initiated through two cell surface serine/threonine kinase receptors, TβRII and TβRI. The predominant TGF-β ligand, TGF-β1, first binds to TβRII, which then recruits and activates TβRI by the constitutively active TβRII kinase. The activated TβRI in turn recruits and activates the transcription factors Smads 2 and 3, also known as rSmads. Nuclear targeting sequences exposed upon activation of rSmads promote their nuclear translocation, either in association with Smad4 or without Smad4, thereby enabling transcriptional activation of numerous TGF-β target genes. An important role for TGF-β in the prostate is strongly implicated by a number of in vivo studies, which demonstrate that androgens negatively regulate expression of TGF-βs, TGF-β receptors, and the activation of rSmads in the prostate. In addition, normal cellular responses to TGF-βs in the prostate are lost during carcinogenesis of this tissue concomitant with loss of TGF-β receptor levels and loss of androgen dependence, implicating a role for TGF-β as a tumor suppressor and regulator of androgen dependence. Using primary prostatic cells lines, our laboratory was first to report that TGF- can directly induce apoptosis of prostatic cells in culture, implicating a role of this cytokine in apoptosis of the prostate following androgen ablation. Thus, an important focus of our work is to understand how TGF-β induces apoptosis.

Numerous protooncogenes and transcription factors have been recently shown to regulate TGF-β signals through a Smad-dependent pathway, many of which interact directly with Smads and modify their biological activity and function. Along these lines our laboratory first reported that androgens intercept TGF-β signals through a direct association of the androgen receptor with Smad3. We have also shown that IGF-I, which has potent tumor promoting properties on the prostate and has been implicated in prostatic carcinogenesis in humans, is an effective inhibitor of TGF-β signaling by selectively blocking the activation of Smad3. Thus, current projects in this laboratory also revolve around understanding the mechanism by which androgens and IGF-I intercept Smad3 function.

We are mainly using three spontaneously immortalized prostatic epithelial cell lines, NRP-152, NRP-154 and DP-153, as models that represent preneoplastic cells or early stage prostate cancer. These cell lines were derived from the preneoplastic dorsolateral prostate of the Lobund-Wistar rat, an animal model that develops prostate cancer with a high incidence and which closely mimic the pathophysiology of the human disease. NRP-152, the best studied of the above cell line, is non-tumorigenic, responsive to androgens, exquisitely responsive to TGF-βs and other growth regulators, and has unique stem cell properties. TGF-βs can promote differentiation, arrest growth, induce apoptosis, and act as tumor suppressors in this cell line model. We recently showed that our newly established non-tumorigenic cell line, DP-153, shares with NRP-152 cells the ability to undergo malignant transformation upon expression of a dominant-negative TβRII, further supporting a role for TGF-β in tumor suppression of this disease.

With the above in vitro and in vivo models our current and future plans involve: 1) Studying the role of PI3-kinase, Akt, Bcl-2 family members, mitochondria, endoplasmic reticulum, and caspases in the induction of apoptosis by TGF-β; and 2) Studying the regulation of TGF-β signaling by EGF, IGF-I, androgens, androgen receptors and androgen receptor co-activators.

SELECTED REFERENCES:

Garcia JA and Danielpour D. Mammalian target of rapamycin inhibition as a therapeutic strategy for urologic malignancies. Mol Cancer Thera, 6:1347-54, 2008.

Yang J, Song K, Krebs TL, Jackson MW, Danielpour D. Rb/E2F4 and Smad2/3 link survivin to TGF-b induced apoptosis and tumor progression. Oncogene, Sep 11;27(40):5326-38, 2008. 2008.

Wang H, Song K, Yang J, Krebs TL, Danielpour D. The LIM protein Hic-5/ARA55 controls TGF-b signaling through a direct physical interaction with Smad7. Oncogene, Nov 20;27(54):6791-805, 2008.

Song K, Wang H, Krebs TL, Danielpour D. Androgenic Control of TGF-β Signaling in Prostate Epithelial Cells through Transcriptional Suppression of TGF-β Receptor II. Cancer Res.;68: 8173-82, 2008.

Yang J, Wahdan-Alaswad R., Danielpour D. Critical role of Smad2 in Tumor Suppression and TGF-b-induced apoptosis of prostate epithelial cells. Cancer Res, 69: 2185-2190, 2009.

Song K, Wang H, Krebs TL. Wang BH, Kelley TJ and Danielpour D. Dihydrotestosterone downregulates expression of Smad3 through a transcriptional mechanism to protect prostate epithelial cells against TGF-β-induced apoptosis. Molecular Endocrinology, 24:2019-2029, 2010.

Wahdan-Alaswad R, Song K, Krebs TL, Sholar DT, Gomez JA, Matsuyama S, and Danielpour D. IGF-I Suppresses BMP Signaling in Prostate Cancer Cells by Activating mTOR Signaling. Cancer Research 70:9106-9117, 2010.

Song, K, Krebs, TL, Danielpour, D. Novel Role of EGF in TGF-b Signaling and Growth Suppression: Mediation by Stabilization of TGF-b Receptor type II. J. Biol. Chem, manuscripts in press, January 2006.

Danielpour, D. and Song, K, Mechanism of Cross-talk between IGF-I and TGF-b, Cytokine and Growth Factor Rev. 17:59-74, 2006.

Song, K, Wang, H, Krebs, TL, Danielpour, D. Novel Roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J, 25:58-60, 2006.

Wang, H, Song, K, Sponseller, TL, Danielpour, D. Novel Function of Androgen Receptor-associated Protein 55/Hic-5 as a Negative Regulator of Smad3 Signaling. J. Biol. Chem., 280:5154-5162, 2005.

Danielpour, D. Functions and Regulation of TGF-b in the Prostate. Euro J. Cancer. 41:840-557, 2005

Song, K, Cornelius, SC, Danielpour, D: Development and characterization of DP-153: a non-tumorigenic prostate epithelial cell line that undergoes malignant transformation by expression of dominant-negative transforming growth factor-beta receptor type II. Cancer Res. 63: 4358-4367, 2003.

Song, K, Cornelius, SC, Reiss, M, Danielpour, D: IGF-I Inhibits Transcriptional Responses of TGF-b by PI3-kinase/AKT-dependent Suppression of the Activation of Smad3 but not Smad2. J. Biol. Chem. 278: 38342- 32351, 2003.

Stewart, LV, Song, K, Hsing AY, Danielpour, D. 2003. Regulation of Trespin expression by modulators of cell growth, differentiation and apoptosis in prostatic epithelial cells. Exp. Cell Res. 284:303-315.

Chipuk, JE, Stewart, LV, Ranieri, A, Song, K, Danielpour, D. 2002. Identification and characterization of a novel rat ov-serpin family member, trespin. J. Biol. Chem. 277: 2612-26421.

Chipuk, JE, Pultz NJ, Cornelius, SC, Jorgensen, JS, Bonham, MJ, Kim SJ, and Danielpour D. 2002. The androgen receptor represses TGF-β signaling through interaction with Smad3. J. Biol. Chem., 277:1240-1248.

Chipuk, JE, Hsing AY, Bhat, MB, Ma, J, Danielpour, D. 2001. BCL-XL regulates TGF-β induced apoptosis in NRP-154 rat prostatic epithelial cells. J Biol. Chem, 276:26614-26621.

Tang, B., de Castro, K., Barnes, H.E., Parks, W.T., Stewart, L., Bottinger, E.P., Wakefield, L.M., and Danielpour, D. 1999. Loss of responsiveness to transforming growth factor beta induces malignant transformation of nontomorigenic rat prostate epithelial cells. Cancer Res., 59:4834-4842.

Danielpour, D. 1999. Transdifferentiation of NRP-152 rat prostatic basal epithelial cells toward a luminal phenotype: regulation by glucocorticoid, insulin-like growth factor-I and transforming growth factor-beta. J. Cell Sci., 112:169-179.

Hayward, S.W., Haughney, P.C., Lopez, E.S. Danielpour, D., and Cuhna, G.R. 1999. The rat prostatic epithelial cell line NRP-152 can differentiate in vivo in response to its stromal environment. Prostate, 39:205-212.

Lucia, M.S., Sporn, M.B., Roberts, A.B., and Danielpour, D. 1998. The role of transforming growth factor-b1, -b2 and -b3 in androgen-responsive growth of NRP-152 rat dorsal prostatic epithelial cells. J. Cell. Physiol., 175:184-192.

Hsing, A.Y., Kadomatsu, K., Bonham, M.J., and Danielpour, D. 1996. Regulation of apoptosis induced by TGF-b1 in non-tumorigenic and tumorigenic rat prostatic epithelial cell lines. Cancer Res., 56:5146-5149.

Danielpour, D., 1996. Induction of transforming growth factor-β autocrine activity by all-transretinoic acid and 1,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells. J. Cell. Physiol., 66:2312-2319.

Danielpour, D., Kadomatsu, K., Anzano, M.A., Smith, J.M., and Sporn, M.B. 1994. Development and characterization of nontumorigenic and tumorigenic epithelial cell lines from rat dorsal-lateral prostate. Cancer Res., 54:3413-3421.