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Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth
Open accessAbstract
Activation of the orphan nuclear receptor TR3/Nur77 (NR4A1) promotes apoptosis and inhibits pancreatic tumor growth, but its endogenous function and the effects of its inactivation have yet to be determined. TR3 was overexpressed in human pancreatic tumors compared with nontumor tissue. Small interfering RNA–mediated knockdown of TR3 or cell treatment with the TR3 antagonist 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) decreased proliferation, induced apoptosis, and decreased expression of antiapoptotic genes including Bcl-2 and survivin in pancreatic cancer cells. Survivin suppression was mediated by formation of a TR3-Sp1-p300 DNA binding complex on the proximal GC-rich region of the survivin promoter. When administered in vivo, DIM-C-pPhOH induced apoptosis and inhibited tumor growth in an orthotopic model of pancreatic cancer, associated with inhibition of the same antiapoptotic markers observed in vitro. Our results offer preclinical validation of TR3 as a drug target for pancreatic cancer chemotherapy, based on the ability of TR3 inhibitors to block the growth of pancreatic tumors. Cancer Res; 70(17); 6824–36. ©2010 AACR.
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Cited by
Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis
Palumbo-Zerr, K., Zerr, P., Distler, A., Fliehr, J., Mancuso, R., Huang, J., Mielenz, D., Tomcik, M., Fürnrohr, B. G., Scholtysek, C., et al. (2015) · Nature Medicine · doi:10.1038/nm.3777 · Cited by 342
FBW7-NRA41-SCD1 axis synchronously regulates apoptosis and ferroptosis in pancreatic cancer cells
Ye, Z., Zhuo, Q., Hu, Q., Xu, X., liu, M., Zhang, Z., Xu, W., Liu, W., Fan, G., Qin, Y., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2020.101807 · Cited by 267
Rodríguez-Calvo, R., Tajes, M., & Vázquez-Carrera, M. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1279146 · Cited by 117
Mohankumar, K., Lee, J., Wu, C. S., Sun, Y., & Safe, S. (2018) · Endocrinology · doi:10.1210/en.2017-03049 · Cited by 24
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Metadata
- Authors
- Lee, S.-O., Abdelrahim, M., Yoon, K., Chintharlapalli, S., Papineni, S., Kim, K., Wang, H., & Safe, S.
- Venue
- Cancer Research
- Published
- 2010-08-31
- Volume
- 70
- Issue
- 17
- Pages
- 6824-6836
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2071366611
- Cited by
- 171
- References
- 0
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- green
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- Lee, S.-O., Abdelrahim, M., Yoon, K., Chintharlapalli, S., Papineni, S., Kim, K., Wang, H., & Safe, S. (2010). Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth. Cancer Research. https://doi.org/10.1158/0008-5472.can-10-1992
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