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2.
Nat Biomed Eng ; 5(11): 1320-1335, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34725507

RESUMEN

In breast cancer, genetic heterogeneity, the lack of actionable targets and immune evasion all contribute to the limited clinical response rates to immune checkpoint blockade therapy. Here, we report a high-throughput screen based on the functional interaction of mouse- or patient-derived breast tumour organoids and tumour-specific cytotoxic T cells for the identification of epigenetic inhibitors that promote antigen presentation and potentiate T-cell-mediated cytotoxicity. We show that the epigenetic inhibitors GSK-LSD1, CUDC-101 and BML-210, identified by the screen, display antitumour activities in orthotopic mammary tumours in mice, that they upregulate antigen presentation mediated by the major histocompatibility complex class I on breast tumour cells and that treatment with BML-210 substantially sensitized breast tumours to the inhibitor of the checkpoint programmed death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid-T-cell screens may help with the identification of candidate immunotherapeutics for a range of cancers.


Asunto(s)
Presentación de Antígeno , Neoplasias de la Mama , Animales , Linfocitos T CD8-positivos , Epigénesis Genética , Femenino , Humanos , Ratones , Organoides
3.
J Clin Invest ; 131(1)2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-32990678

RESUMEN

Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy.


Asunto(s)
Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/inmunología , Proteínas Proteolipídicas Asociadas a Mielina y Linfocito/inmunología , Proteínas de Neoplasias/inmunología , Escape del Tumor , Animales , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Femenino , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos
4.
Arch Biochem Biophys ; 697: 108659, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33144083

RESUMEN

Metabolic reprogramming confers cancer cells plasticity and viability under harsh conditions. Such active alterations lead to cell metabolic dependency, which can be exploited as an attractive target in development of effective antitumor therapies. Similar to cancer cells, activated T cells also execute global metabolic reprogramming for their proliferation and effector functions when recruited to the tumor microenvironment (TME). However, the high metabolic activity of rapidly proliferating cancer cells can compete for nutrients with immune cells in the TME, and consequently, suppressing their anti-tumor functions. Thus, therapeutic strategies could aim to restore T cell metabolism and anti-tumor responses in the TME by targeting the metabolic dependence of cancer cells. In this review, we highlight current research progress on metabolic reprogramming and the interplay between cancer cells and immune cells. We also discuss potential therapeutic intervention strategies for targeting metabolic pathways to improve cancer immunotherapy efficacy.


Asunto(s)
Inmunoterapia/métodos , Neoplasias/metabolismo , Neoplasias/terapia , Animales , Humanos , Inmunidad , Neoplasias/inmunología , Neoplasias/patología
5.
JCI Insight ; 5(9)2020 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-32376804

RESUMEN

Immune checkpoint blockade immunotherapy delivers promising clinical results in colorectal cancer (CRC). However, only a fraction of cancer patients develop durable responses. The tumor microenvironment (TME) negatively impacts tumor immunity and subsequently clinical outcomes. Therefore, there is a need to identify other checkpoint targets associated with the TME. Early-onset factors secreted by stromal cells as well as tumor cells often help recruit immune cells to the TME, among which are alarmins such as IL-33. The only known receptor for IL-33 is stimulation 2 (ST2). Here we demonstrated that high ST2 expression is associated with poor survival and is correlated with low CD8+ T cell cytotoxicity in CRC patients. ST2 is particularly expressed in tumor-associated macrophages (TAMs). In preclinical models of CRC, we demonstrated that ST2-expressing TAMs (ST2+ TAMs) were recruited into the tumor via CXCR3 expression and exacerbated the immunosuppressive TME; and that combination of ST2 depletion using ST2-KO mice with anti-programmed death 1 treatment resulted in profound growth inhibition of CRC. Finally, using the IL-33trap fusion protein, we suppressed CRC tumor growth and decreased tumor-infiltrating ST2+ TAMs. Together, our findings suggest that ST2 could serve as a potential checkpoint target for CRC immunotherapy.


Asunto(s)
Neoplasias Colorrectales/inmunología , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Interleucina-33/inmunología , Microambiente Tumoral/inmunología , Macrófagos Asociados a Tumores/inmunología , Animales , Línea Celular Tumoral , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Macrófagos Asociados a Tumores/citología
6.
Cell Oncol (Dordr) ; 43(1): 81-93, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31512195

RESUMEN

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal subtype of pancreatic cancer, with a 5-year survival rate of < 3%. Early tumor dissemination, late diagnosis and insensitivity to conventional treatment are the major reasons for its high mortality rate. Members of the vascular endothelial growth factor (VEGF) family are overexpressed in PDAC and play important roles in its malignant progression, suggesting that VEGF-targeted therapies may interrupt the proliferation and motility of PDAC cells. Here, we evaluated the anti-tumor activity of cediranib, a pan-VEGF receptor inhibitor, on PDAC cells. METHODS: Anti-proliferative effects of cediranib were determined using cell proliferation and crystal violet staining assays. Annexin V/PI staining, radiation therapy, and cell migration and invasion assays were carried out to examine the effects of cediranib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-tumor activity of cediranib. RESULTS: We found that cediranib decreased PDAC cell proliferation and clonogenic survival and induced apoptotic cell death through inhibition of the anti-apoptotic proteins cIAP1, XIAP, MCL-1 and survivin. Combination with cediranib synergistically increased the sensitivity of PDAC cells to chemotherapeutic agents such as gemcitabine and paclitaxel, and potentiated the effects of radiation therapy on PDAC cell growth inhibition and apoptosis induction. Furthermore, we found that treatment with cediranib impaired PDAC cell migration and invasion via expression reduction of the epithelial-to-mesenchymal transition (EMT) markers ZEB1, N-cadherin and Snail. CONCLUSIONS: Our data indicate that cediranib may exhibit anti-tumor activity in PDAC cells and provide a rationale for further investigation of the potential of VEGF receptor-targeted therapies for the treatment of PDAC.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pancreáticas/metabolismo , Quinazolinas/farmacología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Apoptosis/efectos de la radiación , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Paclitaxel/farmacología , Tolerancia a Radiación , Factores de Transcripción de la Familia Snail/metabolismo , Survivin/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Gemcitabina
7.
Nat Commun ; 9(1): 4718, 2018 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-30413718

RESUMEN

Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.


Asunto(s)
Neoplasias de la Mama/genética , Cromosomas Humanos Par 17/genética , Resistencia a Antineoplásicos/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ARN Helicasas DEAD-box/metabolismo , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Amplificación de Genes/efectos de los fármacos , Humanos , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Nanopartículas/química , Proteína Fosfatasa 2C/genética , Proteína Fosfatasa 2C/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/farmacología , Trastuzumab/uso terapéutico
8.
Anticancer Drugs ; 29(10): 1011-1020, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30096128

RESUMEN

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination are the major reasons for low survival rate in the patients. The bromodomain and extraterminal domain (BET) proteins are known as epigenetic 'readers,' and their inhibitors are novel epigenetic strategies for cancer treatment. Accumulating body of evidence indicates that epigenetic modifications have critical roles in development of EOC, and overexpression of the BET family is a key step in the induction of important oncogenes. Here, we examined the mechanistic activity of I-BET151, a pan-inhibitor of the BET family, in therapy-resistant EOC cells. Our findings showed that I-BET151 diminished cell growth, clonogenic potential, and induced apoptosis. I-BET151 inhibited cell proliferation through down-modulation of FOXM1 and its targets aurora kinase B and cyclin B1. I-BET151 attenuated migration and invasion of the EOC cells by down-regulation of epithelial-mesenchymal transition markers fibronectin, ZEB2, and N-cadherin. I-BET151 synergistically enhanced cisplatin chemosensitivity by down-regulation of survivin and Bcl-2. Our data provide insights into the mechanistic activity of I-BET151 and suggest that BET inhibition has potential as a therapeutic strategy in therapy-resistant EOC. Further in vivo investigations on the therapeutic potential of I-BET151 in EOC are warranted.


Asunto(s)
Carcinoma Epitelial de Ovario/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Proteínas/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Epigénesis Genética/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/patología
9.
Int J Biochem Cell Biol ; 99: 1-9, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29567488

RESUMEN

Epithelial ovarian cancer (EOC) has exhibited marginal improvement in survival rate, despite advances in surgical debulking and chemotherapy regimens. Although the majority of EOC patients achieve a clinical remission after induction therapy, over 80% relapse and succumb to chemoresistant disease. In this regard, it is of paramount importance to elucidate molecular mechanisms and signaling pathways which promote therapy resistance in EOC in order to devise novel and more effective treatment strategies. In this study, we showed that activation of nuclear factor-κB (NF-κB) is significantly higher in therapy-resistant EOC cells compared to chemosensitive counterparts, which was positively associated with resistance to cisplatin, carboplatin, paclitaxel and erlotinib. Bay 11-7082, a highly selective NF-κB inhibitor, reduced cell proliferation, clonogenicity and anoikis resistance in the therapy-resistant EOC cells and induced apoptotic cell death. Moreover, Bay 11-7082 decreased the expression of pro-survival, inflammatory and metastatic genes and synergistically increased anti-proliferative efficacy of cisplatin, carboplatin, paclitaxel and erlotinib. Altogether, these findings suggest that NF-κB is an attractive therapeutic target in EOC to be exploited in translational oncology and Bay 11-7082 is a potential anti-cancer drug to overcome chemoresistance and inhibit proliferation of the EOC cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Neoplasias Ováricas/patología , Anoicis/efectos de los fármacos , Antineoplásicos/farmacología , Femenino , Humanos , FN-kappa B/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Células Tumorales Cultivadas
10.
Sci Rep ; 7(1): 4204, 2017 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-28646172

RESUMEN

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy worldwide. Development of chemoresistance and peritoneal dissemination of EOC cells are the major reasons for low survival rate. Targeting signal transduction pathways which promote therapy resistance and metastatic dissemination is the key to successful treatment. Members of the ErbB family of receptors are over-expressed in EOC and play key roles in chemoresistance and invasiveness. Despite this, single-targeted ErbB inhibitors have demonstrated limited activity in chemoresistant EOC. In this report, we show that dacomitinib, a pan-ErbB receptor inhibitor, diminished growth, clonogenic potential, anoikis resistance and induced apoptotic cell death in therapy-resistant EOC cells. Dacominitib inhibited PLK1-FOXM1 signalling pathway and its down-stream targets Aurora kinase B and survivin. Moreover, dacomitinib attenuated migration and invasion of the EOC cells and reduced expression of epithelial-to-mesenchymal transition (EMT) markers ZEB1, ZEB2 and CDH2 (which encodes N-cadherin). Conversely, the anti-tumour activity of single-targeted ErbB agents including cetuximab (a ligand-blocking anti-EGFR mAb), transtuzumab (anti-HER2 mAb), H3.105.5 (anti-HER3 mAb) and erlotinib (EGFR small-molecule tyrosine kinase inhibitor) were marginal. Our results provide a rationale for further investigation on the therapeutic potential of dacomitinib in treatment of the chemoresistant EOC.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Neoplasias Ováricas/patología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinonas/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Biológicos , Invasividad Neoplásica , Neoplasias Ováricas/genética , Transducción de Señal/efectos de los fármacos
11.
Sci Rep ; 7: 45954, 2017 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-28383032

RESUMEN

Epithelial ovarian cancer (EOC) is the most fatal gynaecological malignancy. Despite initial therapeutic response, the majority of advanced-stage patients relapse and succumb to chemoresistant disease. Overcoming drug resistance is the key to successful treatment of EOC. Members of vascular endothelial growth factor (VEGF) family are overexpressed in EOC and play key roles in its malignant progression though their contribution in development of the chemoresistant disease remains elusive. Here we show that expression of the VEGF family is higher in therapy-resistant EOC cells compared to sensitive ones. Overexpression of VEGFR2 correlated with resistance to cisplatin and combination with VEGFR2-inhibitor apatinib synergistically increased cisplatin sensitivity. Tivozanib, a pan-inhibitor of VEGF receptors, reduced proliferation of the chemoresistant EOC cells through induction of G2/M cell cycle arrest and apoptotic cell death. Tivozanib decreased invasive potential of these cells, concomitant with reduction of intercellular adhesion molecule-1 (ICAM-1) and diminishing the enzymatic activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-2 (MMP-2). Moreover, tivozanib synergistically enhanced anti-tumour effects of EGFR-directed therapies including erlotinib. These findings suggest that the VEGF pathway has potential as a therapeutic target in therapy-resistant EOC and VEGFR blockade by tivozanib may yield stronger anti-tumour efficacy and circumvent resistance to EGFR-directed therapies.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anoicis/efectos de los fármacos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Clonales , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Fase G2/efectos de los fármacos , Humanos , FN-kappa B/metabolismo , Invasividad Neoplásica , Neoplasias Ováricas/patología , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
12.
Sci Rep ; 7: 44075, 2017 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-28287096

RESUMEN

Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anoicis , Neoplasias Encefálicas/complicaciones , Adhesión Celular , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Gefitinib , Glioblastoma/complicaciones , Humanos , Neovascularización Patológica/complicaciones , Neovascularización Patológica/tratamiento farmacológico , Quinazolinas/uso terapéutico
13.
Tumour Biol ; 39(2): 1010428317692255, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28218039

RESUMEN

Arsenic trioxide (As2O3) has been used clinically as an anti-tumor agent. Its mechanisms are mostly considered to be the induction of apoptosis and cell cycle arrest. However, the detailed molecular mechanisms of its anti-cancer action through cell cycle arrest are poorly known. Furthermore, As2O3 has been shown to be a potential DNA methylation inhibitor, inducing DNA hypomethylation. We hypothesize that As2O3 may affect the expression of cell cycle regulatory genes by interfering with DNA methylation patterns. To explore this, we examined promoter methylation status of 24 cell cycle genes in breast cancer cell lines and in a normal breast tissue sample by methylation-specific polymerase chain reaction and/or restriction enzyme-based methods. Gene expression level and cell cycle distribution were quantified by real-time polymerase chain reaction and flow cytometric analyses, respectively. Our methylation analysis indicates that only promoters of RBL1 (p107), RASSF1A, and cyclin D2 were aberrantly methylated in studied breast cancer cell lines. As2O3 induced CpG island demethylation in promoter regions of these genes and restores their expression correlated with DNA methyltransferase inhibition. As2O3 also induced alterations in messenger RNA expression of several cell cycle-related genes independent of demethylation. Flow cytometric analysis revealed that the cell cycle arrest induced by As2O3 varied depending on cell lines, MCF-7 at G1 phase and both MDA-MB-231 and MDA-MB-468 cells at G2/M phase. These changes at transcriptional level of the cell cycle genes by the molecular mechanisms dependent and independent of demethylation are likely to represent the mechanisms of cell cycle redistribution in breast cancer cells, in response to As2O3 treatment.


Asunto(s)
Arsenicales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Metilación de ADN/efectos de los fármacos , Óxidos/farmacología , Antineoplásicos/farmacología , Trióxido de Arsénico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Células MCF-7 , Regiones Promotoras Genéticas
14.
Life Sci ; 167: 67-77, 2016 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-27769816

RESUMEN

AIMS: Cell cycle dysregulation is important in tumorigenesis. Transcriptional silencing of cell cycle regulatory genes, due to DNA methylation, is a common epigenetic event in malignancies. As2O3 has been shown to induce cell cycle arrest and also to be a potential hypomethylating agent. Our study aimed to investigate DNA methylation patterns of cell cycle regulatory genes promoters, the effects of Arsenic trioxide (As2O3) on the methylated genes and cell cycle distribution in colorectal cancer (CRC) cell lines. MAIN METHODS: The methylation-specific PCR (MSP) and/or restriction enzyme-based methods were used to study the promoter methylation patterns of 24 cell cycle regulatory genes in CRC cell lines. Gene expression level and cell cycle distribution were determined by Real-time PCR and flow cytometric analyses, respectively. KEY FINDINGS: Our methylation analysis indicated that only promoters of RBL1 (p107), CHFR and p16 genes were aberrantly methylated in three cell lines. As2O3 significantly decreased DNA methylation in promoter regions of these genes and restored their expression. We found that As2O3 significantly reduced the expression of DNA methyltransferase 1 (DNMT1) and increased arsenic methyltransferase (AS3MT). Furthermore, As2O3 altered transcriptional activity of several unmethylated cell cycle regulatory genes including cyclin B1, E1, D1, GADD45A and p21. Cell cycle flow cytometry analysis showed As2O3 induced G2/M arrest in all three cell lines. SIGNIFICANCE: These data suggest that demethylation and alteration in the expression level of the cell cycle-related genes may be possible mechanisms in As2O3-induced cell cycle arrest in colorectal cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Arsenicales/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Metilación de ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Óxidos/farmacología , Trióxido de Arsénico , Línea Celular Tumoral , Colon/efectos de los fármacos , Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , Humanos , Recto/efectos de los fármacos , Recto/patología , Proteína p107 Similar a la del Retinoblastoma/genética
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