9-cis-Retinoic Acid and Troglitazone Impacts Cellular Adhesion, Proliferation, and Integrin Expression in K562 Cells

Hanson, Amanda; Gambill, Jessica; Phomakay, Venusa; Staten, C. Tyler; Kelley, Melissa D.

doi:10.1371/journal.pone.0093005

Cited by 6 publications

(10 citation statements)

References 73 publications

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“…Conversely, RXR heterodimerization potentiates the actions of several NRs as illustrated in studies combining 9- cis retinoic acid (RXR ligand) with a range of other ligands which has combinatorial effects on cellular phenotypes (11–14) which are mediated through underlying regulation of the global transcriptome(15–18). …”

Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Long

Campbell

2015

Nuclear Receptor Research

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Nuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression.

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Section: Introductionmentioning

confidence: 99%

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Long

Campbell

2015

Nuclear Receptor Research

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“…Adhesion was not mediated by integrin receptors as is traditionally observed with atRA induced cell adhesion [40][41][42]. Of particular note, RAR but not RXR agonism generated a robust adhesion response.…”

Section: Discussionmentioning

confidence: 73%

Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

Whelan

Wang

Chen

et al. 2014

Biochemical and Biophysical Research Communications

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“…Retinoids have been established as having a role in governing integrin-dependent cellular adhesion [ 18 , 35 ]. In K562 cells, retinoids have been demonstrated to restore cellular adhesion to RGD substrates [ 18 ]. However, there is paucity amount of information regarding which retinoid receptors govern cellular adhesion, particularly in K562 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Retinoids have been shown to modulate the integrin repertoire expressed on the cell surface of a number of cell lines, including K562 cells [ 17 , 18 , 35 ]. A number of integrin subunits have been profiled on the K562 cell surface in the presence of 9- cis -RA and recent studies have shown that retinoids are capable of impacting only the α5β1 subset on K562 cells [ 18 ]. Due to the novel adhesion response exhibited by K562 cells, we examined integrin expression of α5 and β1 subunits when K562 cells were exposed to 1 μM RARα, β, or γ agonists or equimolar concentration of vehicle for 24, 48, 72 or 96 hours.…”

Section: Resultsmentioning

confidence: 99%

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Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells

et al. 2017

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The interplay between cellular adhesion and proliferation is complex; however, integrins, particularly the α5β1 subset, play a pivotal role in orchestrating critical cellular signals that culminate in cellular adhesion and growth. Retinoids modify the expression of a variety of adhesive/proliferative signaling proteins including α5β1 integrins; however, the role of specific retinoic acid receptors involved in these processes has not been elucidated. In this study, the effect of all-trans-retinoic acid receptor (RAR) agonists on K562 cellular adhesion, proliferation, and α5β1 integrin cell surface expression was investigated. RARγ agonist exposure increased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin and FN-120 in a time- and concentration dependent manner, while RARα or RARβ agonist treatment had no effect on cellular adhesion. Due to the novel RARγ- dependent cellular adhesion response exhibited by K562 cells, we examined α5 and β1 integrin subunit expression when K562 cells were exposed to retinoid agonists or vehicle for 24, 48, 72 or 96 hours. Our data demonstrates no differences in K562 cell surface expression of the α5 integrin subunit when cells were exposed to RARα, RARβ, or RARγ agonists for all time points tested. In contrast, RARγ agonist exposure resulted in an increase in cell surface β1 integrin subunit expression within 48 hours that was sustained at 72 and 96 hours. Finally, we demonstrate that while exposure to RARα or RARβ agonists have no effect on K562 cellular proliferation, the RARγ agonist significantly dampens K562 cellular proliferation levels in a time- and concentration- dependent manner. Our study is the first to report that treatment with a RARγ specific agonist augments cellular adhesion to α5β1 integrin substrates, increases cell surface levels of the β1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human erythroleukemia cell line.

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9-cis-Retinoic Acid and Troglitazone Impacts Cellular Adhesion, Proliferation, and Integrin Expression in K562 Cells

Cited by 6 publications

References 73 publications

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Pan-Cancer Analyses of the Nuclear Receptor Superfamily

Retinoids induce integrin-independent lymphocyte adhesion through RAR-α nuclear receptor activity

Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells

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