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The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation

Oncogene volume 35, pages 1977–1987 (2016)Cite this article

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Abstract

Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvβ3 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 fluorescently labeled hormones to αvβ3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvβ3) and A2780 (low αvβ3) cells promoted αv and β3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg–Gly–Asp) peptide and neutralizing αvβ3 antibodies, excluding T3-induced β3 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 αv monomer by T3 and of β3 monomer by both hormones and documented a rapid (30–120 min) and dose-dependent (0.1–1000 nM) ERK activation. OVCAR-3 cells and αvβ3-deficient HEK293 cells treated with αvβ3 blockers confirmed 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 β3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly 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 confirmed 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 define a critical role for thyroid hormones as potent αvβ3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

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Acknowledgements

The work of Elena Shinderman Maman and Keren Cohen was done in partial fulfillment of the requirements for a PhD degree and of Chen Weingarten MSc degree from the Sackler Faculty of Medicine, Tel Aviv University, Israel. This work was partially supported by the Li Ka Shing Foundation (LKSF). We are grateful to Professor Jean-Luc Col (Institut Albert Bonniot and Universite' Joseph Fourier, France) for HEK293 β3 and β1 cells.

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Authors and Affiliations

  1. Translational Hemato-Oncology Laboratory, The Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel

    E Shinderman-Maman, K Cohen, C Weingarten, M Ellis & O Ashur-Fabian

  2. Department of Human Molecular Genetics and Biochemistry,

    E Shinderman-Maman, K Cohen, C Weingarten, H Werner & O Ashur-Fabian

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    E Shinderman-Maman, K Cohen, C Weingarten, D Nabriski, H Werner, M Ellis & O Ashur-Fabian

  4. Department of Endocrinology, Meir Medical Center, Kfar-Saba, Israel

    D Nabriski, O Twito & L Baraf

  5. Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA

    A Hercbergs

  6. Department of Medicine, Albany Medical College, Albany, NY, USA

    P J Davis

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Shinderman-Maman, E., Cohen, K., Weingarten, C. et al. The thyroid hormone-αvβ3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation. Oncogene 35, 1977–1987 (2016). https://doi.org/10.1038/onc.2015.262

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