Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Sterle, Helena Andrea; Valli, Eduardo; Cayrol, Florencia; Paulazo, Alejandra; Lamas, Diego José Martinel; Flaqué, María Celeste Díaz; Klecha, Alicia Juana; Colombo, Lucas L.; Medina, Vanina Araceli; Cremaschi, Graciela; Arcos, Marı́a Laura Barreiro

doi:10.1530/joe-14-0159

Cited by 19 publications

(33 citation statements)

References 54 publications

(54 reference statements)

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“…The suppression of p16 gene by the hormones corresponds with results from others showing increased p16 in hypothyroid lymphoma mice model. 88 Similar to our results, T3 has been shown to inhibit IGFBP-6 expression in neuroblastoma cells. 89 However, to the best of our knowledge, our current work is the first to demonstrate hormonal regulation of the GDF-15 gene.…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2015

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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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Section: Discussionsupporting

confidence: 91%

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

et al. 2015

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“…In T-cell lymphomas (TCL), T 3 activates αvβ3 integrin signaling inducing cell proliferation and angiogenesis, in part, via the upregulation of VEGF (Sterle et al 2014, Cayrol et al 2015. Interestingly, a paradoxical effect was found in mouse models inoculated with TCLs, in which high circulating levels of THs favored T lymphoma growth, while hypothyroidism promoted tumor dissemination (Sterle et al 2016).…”

Section: Pi3k/protein Kinase B Pathwaymentioning

confidence: 99%

“…An anti-apoptotic role of THs is also supported by the effect of T 3 on apoptosis regulators. T 3 decreases the cellular abundance of caspases and the proapoptotic Bcl-2-associated X protein (BAX) and increases the expression of the antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) (Zhang et al 2011, Sterle et al 2014. When considering the intrinsic apoptosis pathway, there is evidence that T 3 administration protects hypothyroid rat liver cells from apoptosis induced by oxidative stress in a nontumoral model (Mukherjee et al 2014).…”

Section: Evading Cell Death and Enabling Replicative Immortalitymentioning

confidence: 99%

“…Since then, an impressive expansion of knowledge has established THs as key regulators of several physiological processes, including the embryonic development, growth and metabolism of virtually all tissues (Yen 2001). Additionally, recent data have demonstrated critical roles of THs in cell proliferation, differentiation and survival (Dentice et al 2007, Lin et al 2009, Pascual & Aranda 2013, Romitti et al 2013, Sterle et al 2014, Miro et al 2017.…”

Section: Introductionmentioning

confidence: 99%

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Role of thyroid hormones in the neoplastic process: an overview

Goemann¹,

Romitti²,

Meyer³

et al. 2017

Endocrine-Related Cancer

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Thyroid hormones (TH) are critical regulators of several physiological processes, which include development, differentiation and growth in virtually all tissues. In past decades, several studies have shown that changes in TH levels caused by thyroid dysfunction, disruption of deiodinases and/or thyroid hormone receptor (TR) expression in tumor cells, influence cell proliferation, differentiation, survival and invasion in a variety of neoplasms in a cell type-specific manner. The function of THs and TRs in neoplastic cell proliferation involves complex mechanisms that seem to be cell specific, exerting effects via genomic and nongenomic pathways, repressing or stimulating transcription factors, influencing angiogenesis and promoting invasiveness. Taken together, these observations indicate an important role of TH status in the pathogenesis and/or development of human neoplasia. Here, we aim to present an updated and comprehensive picture of the accumulated knowledge and the current understanding of the potential role of TH status on the different hallmarks of the neoplastic process.

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“…The control of the cell cycle is the most important mechanism for the regulation of cell division. In several cell types, including TCL, THs can modulate the cell cycle, through the regulation of the levels of expression of cyclins, cyclin-dependent kinases and cell cycle inhibitors [43]. In rat GC pituitary cells, T3 induces the acceleration of the G1 phase of the cell cycle leading to an increase of cell proliferation [44].…”

Section: Direct Action Of Ths On Tcl Cells Involves Both Genomic and mentioning

confidence: 99%

Classical and Non-Classical Thyroid Hormone Intracellular Pathways Involved in T Lymphoma Growth

Arcos¹,

Sterle²,

Cayrol³

et al. 2015

IEMAMC

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Thyroid hormones (THs) are important regulators of cell physiology. They are essential for the normal development and growth of mammals, especially for the neural differentiation and the regulation of the metabolism and the immune system. THs also induce the proliferation of several cell types. In human and murine T cell lymphomas (TCL) this effect involves the participation of genomic and nongenomic mechanisms as it was described by the use of free THs and non-cell permeable THs coupled to agarose (TH-ag). The classic actions of thyroid hormones involve the alteration of gene transcription via specific nuclear receptors. The discovery of other effects, independent of this classic mechanism, characterizes a new and non-classic mechanism that involves different signaling pathways. Both, free THs and TH-ag, activate protein kinase C, extracellular signal-regulated kinases and NF-kB and they increase the intracellular calcium levels. However, only the preincubation of T cells with free THs leads to an increased intracellular content of signaling enzymes. T lymphomas display high expression levels of both, the TH nuclear receptors (TRs) and the putative membrane receptor for THs, the integrin V 3, which has been demonstrated to be responsible for THs non-genomic actions. Here, we reviewed the mechanisms involved in THs modulation of the lymphocyte physiology, analyzing the interplay between genomic and nongenomic actions in T cells and its contribution in the development of lymphomas.

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Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

Cited by 19 publications

References 54 publications

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

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

Role of thyroid hormones in the neoplastic process: an overview

Classical and Non-Classical Thyroid Hormone Intracellular Pathways Involved in T Lymphoma Growth

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