Carcinogenesis Advance Access published online on April 13, 2007
Carcinogenesis, doi:10.1093/carcin/bgm088
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Contribution of the Orphan Nuclear Receptor Nur77 to the Apoptotic Action of IGFBP-3
1 Division of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, David Geffen School of Medicine, Los Angeles, CA, USA
2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
* Corresponding author. Mailing address: Division of Pediatric Endocrinology, Mattel Children's Hospital at UCLA, 10833 Le Conte Ave., MDCC 22-315, Los Angeles, CA 90095. Ph: (310) 825-6244 Fax: (310) 206-5843. Email: kukwhalee{at}mednet.ucla.edu (K.-W. L.)
Tumor suppression by Insulin-like growth factor binding protein-3 (IGFBP-3), has been demonstrated to occur via IGF-dependent and –independent mechanisms in vitro and in vivo. We have recently described IGFBP-3 induced mitochondrial translocation of the nuclear receptors RXR
/Nur77 in the induction of prostate cancer cell apoptosis. Herein we demonstrate that IGFBP-3 and Nur77 associate in the cytoplasmic compartment in 22RV1 prostate cancer 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 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 JNK and inhibition of Akt phosphorylation and activity, which have been associated with Nur77 translocation. Finally, IGFBP-3 administration to prostate cancer 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.
Key Words: Insulin-like Growth Factor Binding Protein-3 • Nur77 • apoptosis • prostate cancer
Received September 13, 2006; revised February 28, 2007; accepted March 29, 2007.
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