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Oncogene (2016) 35, 19771987 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16
http://www.nature.com/onc
Web End =www.nature.com/onc
E Shinderman-Maman1,2,3, K Cohen1,2,3, C Weingarten1,2,3, D Nabriski3,4, O Twito4, L Baraf4, A Hercbergs5, PJ Davis6, H Werner2,3, M Ellis1,3 and O Ashur-Fabian1,2,3
Ovarian carcinoma is the fth common cause of cancer death in women, despite advanced therapeutic approaches. v3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of uorescently labeled hormones to v3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high v3) and A2780 (low v3) cells promoted v and 3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (ArgGlyAsp) peptide and neutralizing v3 antibodies, excluding T3-induced 3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the v monomer by T3 and of 3 monomer by both hormones and documented a rapid (30120 min) and dose-dependent (0.11000 nM) ERK activation. OVCAR-3 cells and v3-decient HEK293 cells treated with v3 blockers conrmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the 3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and signicantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have conrmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data dene a critical role for thyroid hormones as potent v3-ligands, driving ovarian cancer cell
Oncogene (2016) 35, 19771987; doi:http://dx.doi.org/10.1038/onc.2015.262
Web End =10.1038/onc.2015.262 ; published online 13 July 2015
INTRODUCTION
Ovarian cancer is the leading cause of gynecological disease-related death. There is a high cure rate for women with the disease localized exclusively to the ovary at the time of diagnosis.13 However, only about one-fth of ovarian cancers are...