scholarly journals STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1058-1064 ◽  
Author(s):  
Qian Zhang ◽  
Hong Y. Wang ◽  
Anders Woetmann ◽  
Puthiyaveettil N. Raghunath ◽  
Niels Odum ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Dna Methyltransferase ◽  
Dna Oligonucleotides ◽  
T Cell Lymphomas ◽  
Molecule Inhibitor ◽  
Epigenetic Gene Silencing ◽  
Cancer Types ◽  
Oncogenic Form

Abstract In this study, we demonstrated that STAT3, a well-characterized transcription factor expressed in continuously activated oncogenic form in the large spectrum of cancer types, induces in malignant T lymphocytes the expression of DNMT1, the key effector of epigenetic gene silencing. STAT3 binds in vitro to 2 STAT3 SIE/GAS-binding sites identified in promoter 1 and enhancer 1 of the DNMT1 gene. STAT3 also binds to the promoter 1 region and induces its activity in vivo. Treatment of the malignant T lymphocytes with STAT3 siRNA abrogates expression of DNMT1, inhibits cell growth, and induces programmed cell death. In turn, inhibition of DNMT1 by a small molecule inhibitor, 5-aza-2-deoxy-cytidine, and 2 DNMT1 antisense DNA oligonucleotides inhibits the phosphorylation of STAT3. These data indicate that STAT3 may in part transform cells by fostering epigenetic silencing of tumor-suppressor genes. They also indicate that by inducing DNMT1, STAT3 facilitates its own persistent activation in malignant T cells. Finally, these data provide further rationale for therapeutically targeting STAT3 in T-cell lymphomas and, possibly, other malignancies.

scholarly journals The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer

Nutrients ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 1269
Author(s):  
Razan J. Masad ◽  
Shoja M. Haneefa ◽  
Yassir A. Mohamed ◽  
Ashraf Al-Sbiei ◽  
Ghada Bashir ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antioxidant Properties ◽  
In Vivo Studies ◽  
Immunomodulatory Effects ◽  
Bioactive Constituents ◽  
Cancer Cell Growth ◽  
Cancer Types ◽  
Immunomodulatory Properties

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

scholarly journals Design of a multi-epitope vaccine against cervical cancer using immunoinformatics approaches

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samira Sanami ◽  
Fatemeh Azadegan-Dehkordi ◽  
Mahmoud Rafieian-Kopaei ◽  
Majid Salehi ◽  
Maryam Ghasemi-Dehnoo ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Lymphocytes ◽  
Tertiary Structure ◽  
Therapeutic Vaccine ◽  
Epitope Prediction ◽  
Therapeutic Effects ◽  
Epitope Vaccine ◽  
In Vivo Experiments

AbstractCervical cancer, caused by human papillomavirus (HPV), is the fourth most common type of cancer among women worldwide. While HPV prophylactic vaccines are available, they have no therapeutic effects and do not clear up existing infections. This study aims to design a therapeutic vaccine against cervical cancer using reverse vaccinology. In this study, the E6 and E7 oncoproteins from HPV16 were chosen as the target antigens for epitope prediction. Cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) epitopes were predicted, and the best epitopes were selected based on antigenicity, allergenicity, and toxicity. The final vaccine construct was composed of the selected epitopes, along with the appropriate adjuvant and linkers. The multi-epitope vaccine was evaluated in terms of physicochemical properties, antigenicity, and allergenicity. The tertiary structure of the vaccine construct was predicted. Furthermore, several analyses were also carried out, including molecular docking, molecular dynamics (MD) simulation, and in silico cloning of the vaccine construct. The results showed that the final proposed vaccine could be considered an effective therapeutic vaccine for HPV; however, in vitro and in vivo experiments are required to validate the efficacy of this vaccine candidate.

scholarly journals Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0136885 ◽  
Author(s):  
Stéphane Kerbrat ◽  
Benoit Vingert ◽  
Marie-Pierre Junier ◽  
Flavia Castellano ◽  
François Renault-Mihara ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Adaptor Protein

4-Acetylantrocamol LT3 Inhibits Glioblastoma Cell Growth and Downregulates DNA Repair Enzyme O6-Methylguanine-DNA Methyltransferase

2021 ◽  
pp. 1-17
Author(s):  
Shih-Yu Lee ◽  
I-Chuan Yen ◽  
Jang-Chun Lin ◽  
Min-Chieh Chung ◽  
Wei-Hsiu Liu
Keyword(s):  
Dna Repair ◽  
Cell Viability ◽  
Colony Formation ◽  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Repair Enzyme ◽  
U251 Cell ◽  
Methylguanine Dna Methyltransferase

Glioblastoma multiforme (GBM) is a deadly malignant brain tumor that is resistant to most clinical treatments. Novel therapeutic agents that are effective against GBM are required. Antrodia cinnamomea has shown antiproliferative effects in GBM cells. However, the exact mechanisms and bioactive components remain unclear. Thus, the present study aimed to investigate the effect and mechanism of 4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from Antrodia cinnamomeamycelium, in vitro. U87 and U251 cell lines were treated with the indicated concentration of 4AALT3. Cell viability, cell colony-forming ability, migration, and the expression of proteins in well-known signaling pathways involved in the malignant properties of glioblastoma were then analyzed by CCK-8, colony formation, wound healing, and western blotting assays, respectively. We found that 4AALT3 significantly decreased cell viability, colony formation, and cell migration in both in vitro models. The epidermal growth factor receptor (EGFR), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Hippo/yes-associated protein (YAP), and cAMP-response element binding protein (CREB) pathways were suppressed by 4AALT3. Moreover, 4AALT3 decreased the level of DNA repair enzyme O6-methylguanine-DNA methyltransferase and showed a synergistic effect with temozolomide. Our findings provide the basis for exploring the beneficial effect of 4AALT3 on GBM in vivo.

scholarly journals A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

2010 ◽  
Vol 9 (5) ◽  
pp. 1136-1146 ◽  
Author(s):  
Kuzhuvelil B. Harikumar ◽  
Ajaikumar B. Kunnumakkara ◽  
Nobuo Ochi ◽  
Zhimin Tong ◽  
Amit Deorukhkar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Kinase ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Growth ◽  
Protein Kinase D ◽  
Molecule Inhibitor

scholarly journals Targeting necroptosis in muscle fibers ameliorates inflammatory myopathies

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Mari Kamiya ◽  
Fumitaka Mizoguchi ◽  
Kimito Kawahata ◽  
Dengli Wang ◽  
Masahiro Nishibori ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Muscle Cell ◽  
Muscle Injury ◽  
Fas Ligand ◽  
Muscle Fibers ◽  
Inflammatory Molecules

AbstractMuscle cell death in polymyositis is induced by CD8+ cytotoxic T lymphocytes. We hypothesized that the injured muscle fibers release pro-inflammatory molecules, which would further accelerate CD8+ cytotoxic T lymphocytes-induced muscle injury, and inhibition of the cell death of muscle fibers could be a novel therapeutic strategy to suppress both muscle injury and inflammation in polymyositis. Here, we show that the pattern of cell death of muscle fibers in polymyositis is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of polymyositis patients and models of polymyositis in vitro and in vivo. Inhibition of necroptosis suppresses not only CD8+ cytotoxic T lymphocytes-induced cell death of myotubes but also the release of inflammatory molecules including HMGB1. Treatment with a necroptosis inhibitor or anti-HMGB1 antibodies ameliorates myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles. Thus, targeting necroptosis in muscle cells is a promising strategy for treating polymyositis providing an alternative to current therapies directed at leukocytes.

scholarly journals MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

2020 ◽  
Author(s):  
Barbara Oldrini ◽  
Nuria Vaquero-Siguero ◽  
Quanhua Mu ◽  
Paula Kroon ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Chemotherapy Resistance ◽  
Glioma Cells ◽  
Promoter Hypermethylation ◽  
Dna Adduct ◽  
Genomic Rearrangements ◽  
Low Grade ◽  
Methylguanine Dna Methyltransferase

AbstractTemozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

scholarly journals Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

2011 ◽  
Vol 4 (4) ◽  
pp. 211
Author(s):  
Serena Meraviglia ◽  
Carmela La Mendola ◽  
Valentina Orlando ◽  
Francesco Scarpa ◽  
Giuseppe Cicero ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Hematologic Malignancies ◽  
Cytolytic Activity ◽  
Cell Therapies ◽  
Stressed Cells

The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.<br />

scholarly journals Modulations of SIR-nucleosome interactions of reconstructed yeast silent pre-heterochromatin by O-acetyl-ADP-ribose and magnesium

2017 ◽  
Vol 28 (3) ◽  
pp. 381-386 ◽  
Author(s):  
Shu-Yun Tung ◽  
Sue-Hong Wang ◽  
Sue-Ping Lee ◽  
Shu-Ping Tsai ◽  
Hsiao-Hsuian Shen ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Chromatin Condensation ◽  
Epigenetic Inheritance ◽  
Assembly System ◽  
Sir Proteins ◽  
Epigenetic Gene Silencing ◽  
In Vitro Assembly ◽  
The Individual

Yeast silent heterochromatin provides an excellent model with which to study epigenetic inheritance. Previously we developed an in vitro assembly system to demonstrate the formation of filament structures with requirements that mirror yeast epigenetic gene silencing in vivo. However, the properties of these filaments were not investigated in detail. Here we show that the assembly system requires Sir2, Sir3, Sir4, nucleosomes, and O-acetyl-ADP-ribose. We also demonstrate that all Sir proteins and nucleosomes are components of these filaments to prove that they are SIR-nucleosome filaments. Furthermore, we show that the individual localization patterns of Sir proteins on the SIR-nucleosome filament reflect those patterns on telomeres in vivo. In addition, we reveal that magnesium exists in the SIR-nucleosome filament, with a role similar to that for chromatin condensation. These results suggest that a small number of proteins and molecules are sufficient to mediate the formation of a minimal yeast silent pre-heterochromatin in vitro.

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