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Carcinogenesis Advance Access originally published online on April 13, 2007
Carcinogenesis 2007 28(8):1653-1658; doi:10.1093/carcin/bgm088
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3

Kuk-Wha Lee*, Laura J. Cobb, Vladislava Paharkova-Vatchkova, Bingrong Liu, Jeffrey Milbrandt1 and Pinchas Cohen

Division of Pediatric Endocrinology, Mattel Children’s Hospital at University of California at Los Angeles, David Geffen School of Medicine, 10833 Le Conte Avenue, MDCC 22-315, Los Angeles, CA 90095, USA
1 Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA

* To whom correspondence should be addressed. Tel: +1 310 825 6244; Fax: +1 310 206 5843;Email: kukwhalee{at}mednet.ucla.edu

Tumor suppression by insulin-like growth factor-binding protein-3 (IGFBP-3) has been demonstrated to occur via insulin-like growth factor-dependent and -independent mechanisms in vitro and in vivo. We have recently described IGFBP-3-induced mitochondrial translocation of the nuclear receptors RXR{alpha}/Nur77 in the induction of prostate cancer (CaP) cell apoptosis. Herein, we demonstrate that IGFBP-3 and Nur77 associate in the cytoplasmic compartment in 22RV1 CaP cells. Nur77 is a major component of IGFBP-3-induced apoptosis as shown by utilizing mouse embryonic fibroblasts (MEFs) derived from Nur77 wild-type and knockout (KO) mice. However, dose–response experiments revealed that a small component of IGFBP-3-induced apoptosis is Nur77 independent. Reintroduction of Nur77 into Nur77 KO MEFs restores full responsiveness to IGFBP-3. IGFBP-3 induces phosphorylation of Jun N-terminal kinase and inhibition of Akt phosphorylation and activity, which have been associated with Nur77 translocation. Finally, IGFBP-3 administration to CaP xenografts on SCID mice induced apoptosis and translocated Nur77 out of the nucleus. Taken together, our results verify an important role for the orphan nuclear receptor Nur77 in the apoptotic actions of IGFBP-3.

Abbreviations: CaP, prostate cancer; IGF, insulin-like growth factor; IGFBP-3, insulin-like growth factor-binding protein-3; JNK, Jun N-terminal kinase; KO, knockout; MEF, mouse embryonic fibroblast; SDS–PAGE, sodium dodecyl sulfate–polyacrylamide gel electrophoresis; TBS, Tris-buffered saline; WT, wild type

Received September 13, 2006; revised February 28, 2007; accepted March 29, 2007.


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G. Zappala, C. Elbi, J. Edwards, J. Gorenstein, M. M. Rechler, and N. Bhattacharyya
Induction of Apoptosis in Human Prostate Cancer Cells by Insulin-Like Growth Factor Binding Protein-3 Does Not Require Binding to Retinoid X Receptor-{alpha}
Endocrinology, April 1, 2008; 149(4): 1802 - 1812.
[Abstract] [Full Text] [PDF]


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