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. 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. 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. Curr Res Pharmacol Drug Discov, 100076, Vol. 3, 2022.
Mamidi MK, Samsa WE, Danielpour D, Chan R, Zhou G. 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. Oncogene, 39:4581-4591, 2020.
Danielpour D*, Purighalla S, Wang, E., Zmina P, Sarkar A. Zhou G. 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. Sci Rep 9(1):11541, PMID: 31395901, 2019.
Lee DK, Liu Y, Liao L, Li W, Danielpour D, Xu J. Cell Research, 29:420-422, 2019.
Shankar E, Song K, Corum S, Wang H, H-Y, Kao and Danielpour D*. . J Biol Chem 291:5512-26, 2016.
Yeh I-Ju, Song K, Danielpour D* and Montano M*. Biochem J. 462(2):315-27, 2014.
Danielpour D*. 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*. PLoS ONE, 2013 8(5):e61896, 2013.
Shola DT, Wang H., Wahdan-Alaswad R and Danielpour D*. Oncogene 31:2480-90, 2012.
Wahdan-Alaswad R, Bane KL, Song K, Krebs TL, Sholar DT, Magi-Galluzzi C, Garcia JA and Danielpour D*. . Mol Cancer Res, 10(6):821-33, 2012.
Song K, Wang H, Krebs TL. Wang BH, Kelley TJ and Danielpour D*. Mol Endocrinol. 24:2019-2029, 2010.
Yang J, Wahdan-Alaswad R., Danielpour D*. . Cancer Res, 69: 2185-2190, 2009.
Garcia JA and Danielpour D*. Mol Cancer Therap, 6:1347-54, 2008.
Song K, Wang H, Krebs TL, Danielpour D*. Cancer Res.;68: 8173-82, 2008.
Wang H, Song K, Yang J, Krebs TL, Danielpour D*. Oncogene, Nov 20;27(54):6791-805, 2008.
Yang J, Song K, Krebs TL, Jackson MW, Danielpour D*. Oncogene, Sept. 11;27(40):5326-38, 2008.
Song, K, Wang, H, Krebs, TL, Danielpour, D*. EMBO J, 25:58-60, 2006.
Song, K, Krebs, TL, Danielpour, D*. J. Biol. Chem, 281: 7765-74, 2006.
Wang, H, Song, K, Sponseller, TL, Danielpour, D*. J. Biol. Chem., 280:5154-5162, 2005.
Song, K, Cornelius, SC, Reiss, M, Danielpour, D*: J. Biol. Chem. 278: 38342- 32351, 2003.
Song, K, Cornelius, SC, Danielpour, D*: Cancer Res. 63: 4358-4367, 2003.
Chipuk, JE, Stewart, LV, Ranieri, A, Song, K, Danielpour, D*: J. Biol. Chem. 277: 26412-26421, 2002.
Chipuk, JE, Cornelius SC, Pultz, NJ, Jorgensen, JS, Bonham, MJ, Kim SJ, Danielpour, D*: J. Biol Chem. 277: 1240-1248, 2002. *corresponding author
Chipuk, JE, Ma, J, Hsing, AY, Bhat, M, Danielpour, D*: J. Biol. Chem. 276:26614-26621, 2001.
Danielpour, D*: J. Cell Science 112:169-179, 1999.
Hayward, SH, Haughney, PC, Lopes, ES, Danielpour, D, Cunha, GR: Prostate 39: 205-212, 1999.
Tang, B, de Castro, K, Barnes, HE, Parks, T, Stewart, L, Bottinger, E, Danielpour, D*, Wakefield, LM*: Cancer Res. 59:4834-4842, 1999. *Authors contributed equally
Lucia, MS, Sporn, MB, Roberts, AB, Danielpour, D*: J. Cell. Physiol. 175:184-192, 1998.
Danielpour, D*: J. Cell. Physiol. 166:231-239, 1996.
Hsing, AY, Kadomatsu, K, Bonham, MJ, Danielpour, D*: Cancer Res. 56:5146-5149, 1996.
Danielpour, D*, Kadomatsu, K, Anzano, MA, Smith, JM, Sporn, MB: Cancer Res. 54:3413-3421, 1994.