Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells

Haque, Azizul; Das, Arabinda; Hajiaghamohseni, Laela M.; Younger, Austin; Banik, Naren L.; Ray, Swapan K.

doi:10.1007/s00262-006-0219-6

Cited by 50 publications

(65 citation statements)

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“…Although it is universally accepted that ATRA can induce apoptosis and inhibit proliferation in glioma cells (4,20,21), the association between the concentration of ATRA and its effects remain unclear. In the present study, ATRA treatment significantly inhibited the proliferation and increased the apoptosis of glioma cells in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

All-trans retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells in vitro

2015

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Abstract. All-trans retinoic acid (ATRA) is a derivative of vitamin A that can induce differentiation and apoptosis, as well as inhibit proliferation, in glioma cells. However, the effect of ATRA on the migration and invasiveness of glioma remains poorly understood. In addition, although it is universally accepted that ATRA can induce apoptosis and inhibit proliferation in glioma cells, the association between the concentration and effects of ATRA remain unclear. Therefore, the present study investigated the effects of ATRA treatment on the migration, invasion, apoptosis and proliferation of glioma cells. The U87 and SHG44 glioma cell lines were treated with various concentrations of ATRA, consisting of 0, 5, 10, 20 and 40 µmol/l. A scratch wound healing assay and a Matrigel invasion assay were used to investigate cell migration and invasion, respectively. Flow cytometry was performed to investigate apoptosis and cell cycle distribution. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to investigate the expression of matrix metalloproteinase (MMP)-2 and -9 in each cell treatment group. Following treatment with ATRA, the migration, invasion and proliferation of the glioma cells were significantly inhibited, and the apoptosis rate was significantly increased compared with that of the blank control group. Furthermore, a dose-effect association was identified between each effects and ATRA treatment. The mRNA and protein expression of MMP-2 in U87 glioma cells was not significantly affected following treatment with low concentrations of ATRA, consisting of 5 and 10 µmol/l ATRA, compared with the expression in the control group (P>0.05). However, treatment with high concentrations of ATRA, consisting of 20 and 40 µmol/l ATRA, significantly downregulated the expression levels of MMP-2 in U87 cells. In contrast to U87 cells, the administration of ATRA treatment to SHG44 glioma cells resulted in a significant and dose-dependent downregulation in MMP-2 mRNA and protein expression (P<0.01). In addition, significant downregulation of MMP-9 expression was identified in the two glioma cell lines (P<0.01). The results of the present study indicate that treatment with ATRA may inhibit migration, invasion and proliferation, and promote apoptosis in glioma cells. Furthermore, the current study indicates that the inhibition of glioma cell invasion by ATRA may be partially associated with its effect ability to downregulate MMP expression.

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Section: Discussionmentioning

confidence: 99%

All-trans retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells in vitro

2015

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“…6.16.DR4, BLS-1.DR4 and THP-1.DR4 cells were then transduced using retroviral vectors for constitutive expression of DM molecules [40,45,47]. Steady-state expression of DM molecules in 6.16.DR4.DM, BLS-1.DR4.DM and THP-1.DR4.DM cells was confirmed by western blot analysis using DM-specific antibody (JSB-DM) [47,48].…”

Section: Cell Linesmentioning

confidence: 99%

“…Western blot analysis 6.16.DR4, 6.16.DR4.DM, BLS-1.DR4, BLS-1.DR4.DM, THP-1.DR4 and THP-1.DR4.DM cell lysates were separated on 4-12% Bis/Tris NuPage gels in MES buffer (Novex; Invitrogen), and analyzed by western blotting for DM (JSB-DM) molecules [36,48].…”

Section: Competitive Peptide Binding Assaysmentioning

confidence: 99%

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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“…Interferon-gamma (IFN-γ) is a homodimeric glycoprotein known to be involved in the immunosurveillance of solid tumors via a combination of lymphocyte mediated immune responses [13]. The direct mode of action of IFN-γ involves significant reduction of DNA synthesis along with induction of apoptosis [14].…”

Section: Introductionmentioning

confidence: 99%

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

2008

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Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and reluctant to apoptosis. N-(4-Hydroxyphenyl) retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-γ) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-γ significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to upregulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-γ should be considered for controlling growth of different human glioblastoma cells.

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Induction of apoptosis and immune response by all-trans retinoic acid plus interferon-gamma in human malignant glioblastoma T98G and U87MG cells

Cited by 50 publications

References 51 publications

All-trans retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells in vitro

All-trans retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells in vitro

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

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