scholarly journals All-trans retinoic acid influences viability, migration and adhesion of U251 glioblastoma cells

2017 ◽  
Vol 69 (4) ◽  
pp. 699-706
Author(s):  
Jelena Marjanovic-Vicentic ◽  
Marija Schwirtlich ◽  
Natasa Kovacevic-Grujicic ◽  
Milena Stevanovic ◽  
Danijela Drakulic
Keyword(s):  
Retinoic Acid ◽  
Cell Morphology ◽  
Neural Differentiation ◽  
Glioblastoma Cells ◽  
Atra Treatment ◽  
Cell Matrix ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Cell Matrix Adhesion ◽  
U251 Cells

Glioblastoma (GBM) is one of the most aggressive and deadly forms of cancer. Literature data reveals that all-trans retinoic acid (ATRA) has anticancer effects on different types of tumor cells. However, data about the effects of ATRA on glioblastoma cells are contradictory. In this study, we examined whether ATRA treatment affects features of human glioblastoma U251 cells. To that end, the cells were treated with different concentrations of ATRA. Results obtained by MTT and the crystal violet assays imply that ATRA affected the viability of U251 glioblastoma cells in a dose- and time-dependent manner. Fluorescence staining of microtubule cytoskeleton protein ?-tubulin revealed that ATRA induced changes in cell morphology. Using semi-quantitative RT-PCR we found that the expression of SOX3 and GFAP genes, as markers of neural differentiation, was not changed upon ATRA treatment. Thus, the observed changes in cell morphology after ATRA treatment are not associated with neural differentiation of U251 glioblastoma cells. The scratch-wound healing assay revealed that ATRA changed the mode of U251 cell migration from collective to single cell motility. The cell-matrix adhesion assay demonstrated that the pharmacologically relevant concentration of ATRA lowered the cell-matrix adhesion capability of U251 cells. In conclusion, our results imply that further studies are needed before ATRA could be considered for the treatment of glioblastoma.

scholarly journals DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 397 ◽  
Author(s):  
Krysta Coyle ◽  
Cheryl Dean ◽  
Margaret Thomas ◽  
Dejan Vidovic ◽  
Carman Giacomantonio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Triple Negative ◽  
Atra Treatment ◽  
Response Elements ◽  
Acid Binding Protein ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

scholarly journals All-Trans Retinoic Acid Enhances Bacterial Flagellin-Stimulated Proinflammatory Responses in Human Monocyte THP-1 Cells by Upregulating CD14

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Thi Xoan Hoang ◽  
Jong Hyeok Jung ◽  
Jae Young Kim
Keyword(s):  
Retinoic Acid ◽  
Cell Surface ◽  
Human Monocyte ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Dependent Manner ◽  
Atra Treatment ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Proinflammatory Responses

All-trans retinoic acid (ATRA), an active form of vitamin A, exerts immunomodulatory functions. In this study, we examined the immune potentiating effect of ATRA on bacterial flagellin-induced NF-κB activation and proinflammatory cytokine production in human monocytic cell line THP-1. ATRA treatment significantly enhanced the flagellin-induced NF-κB/AP-1 activity in THP-1 via the RAR/RXR pathway. Similarly, ATRA enhanced the expression and production of TNF-α and IL-1β in THP-1 cells upon flagellin challenge. The cell surface expression of toll-like receptor 5 (TLR5), which is the receptor for bacterial flagellin, was significantly reduced by ATRA in a concentration- and time-dependent manner. To determine the mechanisms underlying the ATRA-enhanced immune response against bacterial flagellin despite the reduced cell surface expression of TLR5 in ATRA-treated THP-1, we examined the cell surface expression of CD14, which has been proposed to be a TLR co-receptor that enhances the response to microbial components. The cell surface expression of CD14 was significantly enhanced by ATRA treatment, especially in the presence of flagellin. Anti-CD14 antibody treatment prior to ATRA and flagellin treatments completely abolished ATRA-enhanced TNF-α and IL-1β production. Our results suggest that ATRA enhances flagellin-stimulated proinflammatory responses in human monocyte THP-1 cells by upregulating CD14 in a RAR/RXR-dependent manner.

All-Trans Retinoic Acid Accelerates Migration of MOLT3 to SDF-1 α/CXCL12 through the Phosphatidylinositol 3 Kinase (PI3K)/Akt Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4221-4221
Author(s):  
Shiro Jimi ◽  
Taichi Matsumoto ◽  
Junji Suzumiya ◽  
Shuji Hara ◽  
Yasushi Takamatsu ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Actin Polymerization ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Atra Treatment ◽  
Migration Activity ◽  
Hematopoietic Stem ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Phosphatidylinositol 3

Abstract The chemokine stromal cells derived factor-1 (SDF-1)/CXCL12 stimulates lymphocytes, hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) through the corresponding chemokine receptor CXCR4, which modulates homing, retention, and engraftment into the bone marrow. However, regulatory factors for CXCR4 excluding cytokines are totally unknown. Besides, all-trans retinoic acid (ATRA), a drug inducing cell differentiation and apoptosis, increases motility with unknown mechanisms. In the present study, we investigated the intracellular regulatory mechanisms of SDF-1α-induced migration of ATRA-treated cells. We initially surveyed cells exhibiting strongly membrane-associated CXCR4 (M-CXCR4), and found 3 out of 10 different cell lines (MOLT3, U266B1, and Raji). Of those, MOLT3 was identified as the only one enabled to respond to SDF-1α chemoattraction, accompanied by an increase in actin polymerization. When M-CXCR4 in MOLT3 was neutralized or antagonized by an antibody or the antagonist AMD3100, the migration activity to SDF-1α, analyzed using the Boyden chamber method, was totally abolished. ATRA pretreatment for 3 days induced growth inhibition of MOLT3, but apoptosis and differentiation did not occur. ATRA treatment alone had no effects on either CXCR4 gene expression or its total protein expression, and cell motility also did not increase; however, ATRA treatment dose dependently increased M-CXCR4 expression. When SDF-1α was added to the lower chamber, migration activity of cells pretreated by different doses of ATRA increased dose dependently and reached up to 5 times greater compared with cells lacking ATRA pretreatment. The increased migration activity was blocked by wortmannin, which inhibits phosphatidylinositol 3 kinase (PI3K), AKT inhibitor, and cytochalasin D, which inhibits actin polymerization; U0126, an inhibitor of MEK1/2, did not block the effects of ATRA and SDF-1α. The results indicate that M-CXCR4 is quite important for cell migration, and the intracellular signaling for the M-CXCR4/SDF-1 axis primarily involves the PI3K/Akt pathway, which ATRA positively affected. This is the fist time to show that migration activity to SDF-1 was accelerated by ATRA. Clinical application of this phenomenon may help to augment HSC/HPC homing after transplantation.

scholarly journals Thrombocytosis in a patient with acute promyelocytic leukemia during treatment with all-trans retinoic acid and arsenic trioxide

2020 ◽  
Author(s):  
Maryam Habibi ◽  
Reza Manouchehri Ardekani ◽  
Hossein Motedayyen
Keyword(s):  
Retinoic Acid ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Side Effect ◽  
Promyelocytic Leukemia ◽  
Atra Treatment ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Thrombocytosis, an uncommon side effect of all-trans retinoic acid (ATRA) treatment, occurs in some patients with acute promyelocytic leukemia. Our case showed thrombocytosis on day 26 to day 32 of ATRA and arsenic trioxide therapies and then started to decrease gradually without changing ATRA dosage. Thrombocytosis may associate with cytokine.

scholarly journals Proof of differentiative mode of action of all-trans retinoic acid in acute promyelocytic leukemia using X-linked clonal analysis

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1916-1919 ◽  
Author(s):  
S Elliott ◽  
K Taylor ◽  
S White ◽  
R Rodwell ◽  
P Marlton ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Mechanism Of Action ◽  
Clonal Analysis ◽  
Promyelocytic Leukemia ◽  
Atra Treatment ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Using X-linked clonal analysis, mechanism of action of all-trans retinoic acid (ATRA) was sought in a 16-year-old female with relapsed clonally evolved acute promyelocytic leukemia (APL), who achieved complete remission. On ATRA, metamorphosis of peripheral blood leukemic promyelocytes to mature neutrophils was observed, despite the persistence of t(15;17) in 100% of bone marrow metaphases. DNA was extracted from fractionated serial blood specimens, collected at diagnosis, in first complete remission (CR), relapse, and during ATRA treatment. Using a phosphoglycerokinase (PGK) probe, the patient was heterozygous for both Bgl I and Bst XI PGK polymorphisms. Methylation analysis showed monoclonal leukemic promyelocytes with a polyclonal first CR achieved by standard chemotherapy. Subsequent examination, in relapse, of granulocytes appearing during ATRA treatment showed these to be monoclonal, proving these were derived from the neoplastic clone. The X-linked clonal analysis methodology has provided in vivo evidence of cellular differentiation as the mechanism of action of ATRA. Parallel studies of cytogenetic and clonal analysis showed a regression of the t(15;17) cytogenetic abnormality and return of a polyclonal PGK methylation pattern in 5 weeks, indicating a repopulation of marrow by normal stem cells. As standard cytogenetic techniques are inappropriate for nondividing cells, X-linked clonal analysis provides a marker system to allow insight into mechanism of drug action in malignant hematologic disease.

Induction of Both CCAAT/Enhancer Binding Protein β and ε Are Required for All Trans Retinoic Acid-Induced Granulocytic Differentiation of Myeloid Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3459-3459
Author(s):  
Min Lu ◽  
Lijuan Xia ◽  
Alan D. Friedman ◽  
Samuel Waxman ◽  
Yongkui Jing
Keyword(s):  
Retinoic Acid ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Atra Treatment ◽  
Granulocytic Differentiation ◽  
Differentiation Induction ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Enhancer Binding Protein

Abstract All trans retinoic acid (ATRA) induces remission in patients with acute promyelocytic leukemia (APL) by induction of granulocytic differentiation. Since CCAAT/enhancer binding protein (C/EBP) α, β and ε play important roles in normal granulocytic differentiation we compared their expression and regulation in ATRA differentiation inducible NB4 and HL-60 cells to their ATRA differentiation resistant subclones R4 and HL-60/Res cells. All four cell lines robustly express C/EBPα but have low or absent C/EBPβ and ε expression. ATRA treatment increases the levels of C/EBPβ and ε protein in NB4 and HL-60 cells but not in the R4 and HL-60/Res cells which is correlated with the degree of differentiation induction. Knockdown of C/EBPβ or ε using shRNA decreases ATRA differentiation induction of HL-60 cells. HL-60 cells with BCR-ABL stable transfection lose expression of C/EBPα, and ATRA-induced differentiation and expression of C/EBPβ and ε are no longer seen. K562 cells which express BCR-ABL do not have detectable or inducible C/EBPα, β and ε after ATRA treatment and are resistant to ATRA differentiation induction. Ectopic expression of C/EBPα-estrogen receptor (ER) or C/EBPβ-ER, but not C/EBPε-ER, induces granulocytic differentiation in K562 cells after addition of estradiol or tamoxifen which activates these fusion factors. C/EBPα-ER or C/EBPβ-ER infected K562 cells is followed by induction of C/EBPε expression and knockdown of C/EBPε in C/EBPα-ER or C/EBPβ-ER infected K562 cells decreases induction of differentiation. The induction of C/EBPα, β, and ε expression by ATRA is investigated in ten additional myeloid leukemia cell lines and it is found that the expression of C/EBPβ and ε, but not C/EBPα, are induced in THP-1 and ML-1 cells which are responsive to ATRA differentiation induction. These results indicate that induction of C/EBPβ is required and C/EBPε plays a collaborative role with C/EBPβ in ATRA-induced differentiation of myeloid leukemia cells.

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