Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone

Abstract

Thyroid hormone induces tumor cell and blood vessel cell proliferation via a cell surface receptor on heterodimeric integrin αvβ3. We investigated the role of thyroid hormone-induced internalization of nuclear integrin αv monomer. Physiological concentration of thyroxine (free T4, 10(-10) M), but not 3,5,3'-triiodo-l-thyronine (T3), induced cellular internalization and nuclear translocation of integrin αv monomer in human non-small-cell lung cancer (H522) and ovarian carcinoma (OVCAR-3) cells. T4 did not complex with integrin αv monomer during its internalization. The αv monomer was phosphorylated by activated ERK1/2 when it heterodimerized with integrin β3 in vitro. Nuclear αv complexed with transcriptional coactivator proteins, p300 and STAT1, and with corepressor proteins, NCoR and SMRT. Nuclear αv monomer in T4-exposed cells, but not integrin β3, bound to promoters of specific genes that have important roles in cancer cells, including estrogen receptor-α, cyclooxygenase-2, hypoxia-inducible factor-1α, and thyroid hormone receptor β1 in chromatin immunoprecipitation assay. In summary, monomeric αv is a novel coactivator regulated from the cell surface by thyroid hormone for the expression of genes involved in tumorigenesis and angiogenesis. This study also offers a mechanism for modulation of gene expression by thyroid hormone that is adjunctive to the nuclear hormone receptor (TR)-T3 pathway.

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

“…The mechanisms by which thyroid hormones regulate genes transcription via the integrin have recently been clarified in part in the lung and ovarian cancer cells; here, the cellular trafficking of the αv monomer to the nucleus and its function as a transcription factor for an array of genes has been demonstrated. 62 This trafficking event was also shown to be ERK-dependent. 62 Given that the activation of ERK has been closely correlated with the thyroid hormonal action in cancer cells, 17,18,26,[28][29][30][63][64][65][66][67][68][69] together with the central role of MAPK in ovarian cancer, 70 led us to explore this pathway in our experimental system.…”

Nanotetrac targets integrin αvβ3 on tumor cells to disorder cell defense pathways and block angiogenesis

“…Finally, agonist thyroid hormone induces internalization of αvβ3 45. This was initially interpreted by us to reflect the known recycling of the integrin46 but is now recognized to be relevant to gene expression.…”

“…Tetrac blocked internalization of αvβ3, and we subsequently found that T 4 directed the αv monomer, but not β3, into the cell nucleus. In the nucleus, αv was found to function as a coactivator, supporting transcription of several genes that are important to cancer cell biology, including HIF-1α and the estrogen receptor ( ER α) 45. Thus, the thyroid hormone–tetrac receptor on αvβ3 has a variety of functions mediated by the intact heterodimer, but the interaction of hormone and αvβ3 is capable of changing the structure and function of the integrin.…”

Novel aspects of T3 actions on GH and TSH synthesis and secretion: physiological implications

“…The non-genomic or posttranscriptional actions of THs are not dependent on the nuclear receptor interaction with TRE, even though the signaling resulting from these mechanisms could lead to the regulation of gene expression (Davis et al 2013(Davis et al , 2016. These actions are rapidly triggered even in the presence of transcription inhibitors (Yusta et al 1998, Lorenzo et al 2002 by TH interactions with THRs coupled to specific enzymes in the cytosol or to other binding sites located on the plasma membrane and organelles such as mitochondria and endoplasmic reticulum (Moeller et al 2006, Davis et al 2008, 2009, Goulart-Silva et al 2011.…”

“…Other genes/proteins that are targeted by T 3 also present an overlap of non-genomic and genomic mechanisms. The T 4 -αVβ3 interaction promotes αVβ3 internalization (Lin et al 2013) and the αV monomer forms a complex with MAPK-p300 inside the cell that binds to the Thrb1 promoter increasing its transcriptional rate (Hammes & Davis 2015). The increased amount of THRB1, in turn, increases the response to genomic actions of T 3 mediated by this isoform (Hammes & Davis 2015).…”