TY - JOUR
T1 - Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3
AU - Lee, Kuk Wha
AU - Cobb, Laura J.
AU - Paharkova-Vatchkova, Vladislava
AU - Liu, Bingrong
AU - Milbrandt, Jeffrey
AU - Cohen, Pinchas
N1 - Funding Information:
The authors wish to thank David Hwang and George Lin for expert technical assistance. We are also grateful to Dr X.-k.Zhang for providing the Nur77 coding sequence. This work was supported in part by a CaP Foundation award and National Institutes of Health Grants RO1AG20954, P50CA92131 and RO1CA100938 (to P.C.); grants from the Stein-Oppenheimer Foundation, the Lawson Wilkins Pediatric Endocrinology Society, University of California, Los Angeles, CaP SPORE Career Development Award, National Institutes of Health Grant 2K12HD34610 (to K.-W.L.) and a Department of Defense awards PC050754 (to L.J.C) and PC061077 (to K.-W.L.).
PY - 2007/8
Y1 - 2007/8
N2 - 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 RXRα/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.
AB - 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 RXRα/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.
UR - http://www.scopus.com/inward/record.url?scp=34548069891&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgm088
DO - 10.1093/carcin/bgm088
M3 - Article
C2 - 17434920
AN - SCOPUS:34548069891
SN - 0143-3334
VL - 28
SP - 1653
EP - 1658
JO - Carcinogenesis
JF - Carcinogenesis
IS - 8
ER -