David Danielpour, PhD, is a Professor of Cancer Research at the Case Comprehensive Cancer Center, with secondary appointments in the Department of Pharmacology at SOM and the Department of Urology at the University Hospital of Cleveland. Danielpour received a BS in Biology from Syracuse University, Syracuse, NY, an MA (Thesis in Developmental Biology) from the University of New York College at Buffalo, and a PhD in Biochemistry and Molecular Biology (Dissertation on Autocrine Control of Mammary Tumor Growth) from the Graduate School of Biomedical Sciences (GSBS) at the University of Texas School of Medicine in Houston, TX. In May of 1987, he joined Dr. Michael Sporn’s research group as a Guest Researcher at the Laboratory of Chemoprevention (NCI, NIH, Bethesda, MD), where he studied the biology of transforming factor-βs (TGF-βs), particularly their regulation of their function and expression in various normal and tumorigenic cell types. While at the NCI, Danielpour developed the first most sensitive and specific sandwich enzyme-linked immunosorbent assays for the identification and quantification of each of the three mammalian TGF-β isoforms in complex biological fluids. He also developed and characterized three rat prostate epithelial cell lines, one of which is named NRP-152, which has unique stem cell-type properties. In collaboration with Simon Hayward at Gerald Cunha’s laboratory at UCSF, the NRP-152 cell line was shown to develop into prostate ductal structures in vivo when implanted with urogenital sinus mesenchyme. In September 1991, he was promoted to the rank of Senior Staff Fellow at the NCI, where he started his research program in prostate cancer, with a specific focus on TGF-β. In October 1988, Danielpour was recruited to the Case Comprehensive Cancer Center as an Associate Professor in the tenure track to continue his TGF-β research. He received the award of tenure in June 2005 and was promoted to Full Professor with tenure in 2012. Danielpour has authored over 126 peer-reviewed publications.
My lab focuses on function and regulation of TGF-ß and BMP in the prostate and prostate cancer, as well as oncogenic function of JAB1, therapeutic control of IGF-I/PI3K/Akt/mTOR and AMPK signaling.
David Danielpour's Biography
Teaching Information
Teaching Schedule
Course Director and Instructor of BIOC 360/460: Advanced Technologies for Cancer Research
Course Director and Instructor of PATH 418: Tumor Immunology
Faculty Facilitator for IBMS 500: On Being a Professional Scientist
Faculty Facilitator of inquiry groups (IQ) for first- and second-year medical students. Topics: the human blueprint, oncology, the GI system, nutrition, energy metabolism & biochemistry, hepatology, homeostasis & host response, pharmacology, cardiology & cardiovascular system, renal physiology & pathology, pulmonary physiology & pathology, shock, host defense, immunology, endocarditis, mucosal immunity & abdominal infections, pathogens, infectious diseases, immunodeficiencies, anemias, hematology, blood disorders, connective tissue disorders, arthritis, muscular-skeletal disorders, trauma, skin malignancies, neurology, psychology, psychiatry
Instructor for DEN 516 at the School of Dental Medicine: Microbiology Immunology and Immune System
Instructor for HEWB 128 at the School of Dental Medicine: Body as Host: Dental Immunology, Pathogens, Oral Cancer
Lecturer for Radiation Oncology Residents, University Hospitals
Research Information
Research Interests
- Role of TGF-β as a tumor suppressor and tumor promoter of the prostate.
- Control of TGF-β signaling and its regulation in prostate cancer.
- Crosstalk of TGF-β signaling with IGF-I/PI3K/AKT/mTORC1 signaling.
- Crosstalk of TGF-β signaling with androgen receptor (AR) signaling in prostate epithelial cells.
- Role of Hic-5 (ARA55) in control of TGF- β and BMP responses in prostate cancer.
- Roles of BCL-2 family members of Survivin in TGF-β-induced apoptosis and gene expression.
- Role of AMPK and mTORC1 as mediators of the cellular responses to Sepantronium Bromide (YM155).
- Control of the NOTCH ligand Jagged 1 by mTOR, Akt, and TGF-β1 in renal cancer.
- Tumor hypoxia in cancer properties and cancer therapeutics.
- Oncogenic function of JAB1/COPS5 in prostate cancer progression.
Research Projects
TGF-β as a Tumor Suppressor and Regulator in the Prostate: One area my laboratory focuses on is the role of transforming growth factor-beta (TGF-β) as a tumor suppressor and regulator of growth, apoptosis, and androgenic responses in the prostate. Previous in vivo studies suggest that androgens negatively regulate TGF-β expression, its receptors (TβRI and TβRII), and Smad activation (Smads 2 and 3) in the prostate. During prostatic carcinogenesis, normal TGF-β responses are lost or altered, coinciding with reduced receptor levels and loss of androgen dependence. This suggests that TGF-β signaling plays a key role in maintaining androgen dependence and tumor suppression. To explore this, in a collaborative effort with Dr. Lalage Wakefield’s group at the NCI, we disrupted TGF-β receptor function in non-tumorigenic rat prostate epithelial cell lines (NRP-152 and DP-153) by overexpressing a truncated TβRII, which acts as a dominant-negative receptor (DNR). Using retroviral transduction, we found that DNR expression induced malignant transformation of those non-tumorigenic, leading to tumor growth in athymic mice. This supported the role of TGF-β as a tumor suppressor in the prostate.
TGF-β Induces Apoptosis in Prostatic Cells: Our lab was the first to demonstrate that TGF-β can directly induce apoptosis in isolated prostatic cells. We have since focused on understanding how TGF-β triggers apoptosis and how this mechanism is altered in prostate cancer. Our studies show that TGF-β induces cytochrome c release, leading to caspase-9 and -3 activation. Additionally, TGF-β downregulates the anti-apoptotic proteins Bcl-xl and survivin.
Survivin Suppression by TGF-β Signaling: Survivin, an inhibitor of apoptosis protein (IAP), is strongly linked to aggressive prostate cancer and treatment resistance. We found that an intact TGF-β signaling pathway in pre-neoplastic prostate cells suppresses survivin expression by activating retinoblastoma protein (Rb) and related pocket proteins via a Smad-dependent mechanism. These proteins then interact with CHR and CDE elements in the survivin promoter to suppress survivin gene expression.
Mechanisms of TGF-β Resistance in Prostate Cancer: Another major focus has been to understand how prostate cancer cells evade TGF-β-mediated tumor suppression. We identified key pathways that contribute to this resistance, including:
- Androgen receptor (AR) activation
- IGF-I/PI3K/Akt/mTOR signaling
- Rb inactivation
- LIM domain protein Hic-5 expression
Our lab was the first to show that IGF-I promotes proliferation and survivin expression in NRP-152 cells by blocking autocrine TGF-β signaling, leading to Cyclin D suppression and Rb inactivation. IGF-I also inhibits TGF-β receptor signaling via Akt1 and mTORC1. Akt1 directly interacts with Smads 2 and 3, preventing gene regulation, while mTORC1 inhibition restores TGF-β responses. These mechanisms may contribute to the shift of TGF-β from tumor suppressor to oncogene in late-stage cancers. Additionally, we discovered that Smad2 is a critical tumor suppressor in prostate epithelial cells, as silencing its expression alone promotes malignant transformation.
Current Research and Future Directions
- Analyzing YM155, a potent survivin inhibitor, in prostate and renal cancer cells.
- Investigating how hypoxia suppresses early YM155 signaling.
- Examining the oncogenic role of Jab1/COPS5 in prostate cancer.
- Studying Jagged1’s compensatory role in mTOR inhibitor responses in renal cell carcinoma.
Publications
Selective Peer-Reviewed Publications
Danielpour, D. Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective. Pharmaceuticals, MDPI, 2024 Apr 20;17(4):533. doi: 10.3390/ph17040533. 71 pages review; cited 21 times in the first 10 months of publication.
Danielpour D*, Corum S, Leahy P, Bangalore A. Jagged1 is induced by mTOR inhibitors in renal cancer cells through an Akt/ALK/Smad4-dependent mechanism. Curr Res Phamacol Drug Discov. 2022. Curr Res Pharmacol Drug Discov. 2022 Jul 4;3:100117. doi: 10.1016/j.crphar.2022.100117. eCollection 2022.
Danielpour D*, Corum S, Welford SM, and Shankar E. Hypoxia represses early responses of prostate and renal cancer cells to YM155 independent of HIF-1α and HIF-2α. Curr Res Pharmacol Drug Discov, 100076, Vol. 3, 2022.
Mamidi MK, Samsa WE, Danielpour D, Chan R, Zhou G. The transcriptional cofactor JAB1/COPS5 serves as a Potential Oncogenic Hub of Human Chondrosarcoma Cells In Vivo. Am J Cancer Res, 11: 5056-5075, 2021.
Samsa WE, Mamidi MK, Bashur L, Elliott R, Miron A, Chen Y, Lee BH, Chan R, Danielpour D, Zhou G. The Crucial p53-Dependent Oncogenic Role of Jab1 in Osteosarcoma Pathogenesis. Oncogene, 39:4581-4591, 2020.
Danielpour D*, Purighalla S, Wang, E., Zmina P, Sarkar A. Zhou G. Jab1 is an oncogenic target in prostate cancer. Biochem Biophys Res Commun. 518(2): 374-380, 2019.
Danielpour D*, Gao Z., Zmina P., Shankar E., Shultes B , Mr. Raul Jabova , Dr. Scott Welford , Maria Hatzoglou. Early Cellular Responses of Prostate Carcinoma Cells to Sepantronium Bromide (YM155) Involve Suppression of mTORC1 by AMPK. Sci Rep 9(1):11541, PMID: 31395901, 2019.
Lee DK, Liu Y, Liao L, Li W, Danielpour D, Xu J. Neuroendocrine prostate carcinoma cells originate from the p63-expressing basal cells but not the pre-existing adenocarcinoma cells in mice. Cell Research, 29:420-422, 2019.
Shankar E, Song K, Corum S, Wang H, H-Y, Kao and Danielpour D*. Signaling Network Controlling Androgenic Repression of c-Fos in Prostate Adenocarcinoma Cells. J Biol Chem 291:5512-26, 2016.
Yeh I-Ju, Song K, Danielpour D* and Montano M*. HEXIM1 in Castrate-Resistant Prostate Cancer. Biochem J. 462(2):315-27, 2014.
Danielpour D*. Transforming Growth Factor-beta (TGF-β) in Prostate Cancer. Tindall D. (ed). In: Prostate Cancer: Biochemistry, Molecular Biology and Genetics. New York, NY: Springer Science + Business Media, Protein Reviews 16: 207-242, 2013.
Song K, Shankar E, Yang J, Bane KL, Wahdan-Alaswad RS, and Danielpour D*. Critical role of a Survivin/TGF-β/mTORC1 Axis in IGF-I-Mediated Growth of Prostate Epithelial Cells. PLoS ONE, 2013 8(5):e61896, 2013.
Shola DT, Wang H., Wahdan-Alaswad R and Danielpour D*. Hic-5 Controls BMP4 Responses in Prostate Cancer Cells through Interacting with Smads 1, 5 and 8. Oncogene 31:2480-90, 2012.
Wahdan-Alaswad R, Bane KL, Song K, Krebs TL, Sholar DT, Magi-Galluzzi C, Garcia JA and Danielpour D*. Inhibition of mTORC1 Kinase Activates Smads 1 and 5 but not Smad8 in Human Prostate Cancer Cells, Mediating Cytostatic Response to Rapamycin. Mol Cancer Res, 10(6):821-33, 2012.
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. Mol Endocrinol. 24:2019-2029, 2010.
Yang J, Wahdan-Alaswad R., Danielpour D*. Critical role of Smad2 in Tumor Suppression and TGF-β-induced apoptosis of prostate epithelial cells. Cancer Res, 69: 2185-2190, 2009.
Garcia JA and Danielpour D*. Mammalian target of rapamycin inhibition as a therapeutic strategy for urologic malignancies. Mol Cancer Therap, 6:1347-54, 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.
Wang H, Song K, Yang J, Krebs TL, Danielpour D*. The LIM protein Hic-5/ARA55 controls TGF-β signaling through a direct physical interaction with Smad7. Oncogene, Nov 20;27(54):6791-805, 2008.
Yang J, Song K, Krebs TL, Jackson MW, Danielpour D*. Rb/E2F4 and Smad2/3 link Survivin to TGF-β induced apoptosis and tumor progression. Oncogene, Sept. 11;27(40):5326-38, 2008.
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.
Song, K, Krebs, TL, Danielpour, D*. Novel Role of EGF in TGF-β Signaling and Growth Suppression: Mediation by Stabilization of TGF-β Receptor type II. J. Biol. Chem, 281: 7765-74, 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.
Song, K, Cornelius, SC, Reiss, M, Danielpour, D*: IGF-I Inhibits Transcriptional Responses of TGF-β by PI3-kinase/AKT-dependent Suppression of the Activation of Smad3 but not Smad2. J. Biol. Chem. 278: 38342- 32351, 2003.
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.
Chipuk, JE, Stewart, LV, Ranieri, A, Song, K, Danielpour, D*: Identification and characterization of a novel rat ov-serpin family member, trespin. J. Biol. Chem. 277: 26412-26421, 2002.
Chipuk, JE, Cornelius SC, Pultz, NJ, Jorgensen, JS, Bonham, MJ, Kim SJ, Danielpour, D*: The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. J. Biol Chem. 277: 1240-1248, 2002. *corresponding author
Chipuk, JE, Ma, J, Hsing, AY, Bhat, M, Danielpour, D*: Bcl-xL, blocks TGF-β1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf-1-dependent caspase activation in NRP-154 prostatic epithelial cells. J. Biol. Chem. 276:26614-26621, 2001.
Danielpour, D*: 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 Science 112:169-179, 1999.
Hayward, SH, Haughney, PC, Lopes, ES, Danielpour, D, Cunha, GR: The rat prostatic epithelial cell line NRP-152 can differentiate in vivo in response to stromal environment. Prostate 39: 205-212, 1999.
Tang, B, de Castro, K, Barnes, HE, Parks, T, Stewart, L, Bottinger, E, Danielpour, D*, Wakefield, LM*: Loss of responsiveness to TGF-β induces malignant transformation of nontumorigenic rat prostate epithelial cells. Cancer Res. 59:4834-4842, 1999. *Authors contributed equally
Lucia, MS, Sporn, MB, Roberts, AB, Danielpour, D*: The role of transforming growth factor-ß1, ß2 and ß3 in androgen-responsive growth of NRP-152 rat prostatic epithelial cells. J. Cell. Physiol. 175:184-192, 1998.
Danielpour, D*: Induction of transforming growth factor-β autocrine activity by all-trans-retinoic acid and 1alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells. J. Cell. Physiol. 166:231-239, 1996.
Hsing, AY, Kadomatsu, K, Bonham, MJ, Danielpour, D*: Regulation of apoptosis induced by TGF-ß1 in nontumorigenic and tumorigenic rat prostatic epithelial cells lines. Cancer Res. 56:5146-5149, 1996.
Danielpour, D*, Kadomatsu, K, Anzano, MA, Smith, JM, Sporn, MB: Development and characterization of nontumorigenic and tumorigenic epithelial-cell lines from rat dorsal-lateral prostate. Cancer Res. 54:3413-3421, 1994.