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

Abstract:

: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 RXRalpha/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.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Lee KW,Cobb LJ,Paharkova-Vatchkova V,Liu B,Milbrandt J,Cohen P

doi

10.1093/carcin/bgm088

subject

Has Abstract

pub_date

2007-08-01 00:00:00

pages

1653-8

issue

8

eissn

0143-3334

issn

1460-2180

pii

bgm088

journal_volume

28

pub_type

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