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1.
Nat Commun ; 11(1): 2978, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532977

RESUMO

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.

2.
Asian Pac J Cancer Prev ; 21(5): 1207-1212, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32458623

RESUMO

The socioeconomic burden of cancer is growing rapidly in the Asian region, with a concentrated burden on low- and middle- income countries. The residents of this region, representing almost 60% of the global population, demonstrate an eclectic and complex nature, with huge disparities in ethnicity, sociocultural practices among others. The Asian National Cancer Centers Alliance (ANCCA) was established in 2005 by heads of several national cancer centers (NCCs) in the region to address common issues and concerns among Asian countries. During the first 13 years of ANCCA's existence, the participating NCCs' senior managers paved the way toward collaboration through transparent sharing of key facts and activities. Concrete achievements of the Alliance include the Asia Tobacco-Free Declaration, the establishment of the ANCCA Constitution in 2014 as well as the creation of an official website more recently. In November 2019, the most active ANCCA members (China, India, Indonesia, Japan, Korea, Mongolia, Singapore, Thailand, and Vietnam) strengthened the bonds of the entity with the clear aim to halt the increase in cancer and mortality rates in Asian countries by 2030. New opportunities including accelerated cooperation between members as well as collaboration with external and multidisciplinary stakeholders at local, regional and international levels are an essential step to most effectively tackle cancers in Asia.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32272509

RESUMO

Objective: Radiation is known to induce autophagy in malignant glioma cells whether it is cytocidal or cytoprotective. Dexamethasone is frequently used to reduce tumor-associated brain edema, especially during radiation therapy. The purpose of the study was to determine whether and how dexamethasone affects autophagy in irradiated malignant glioma cells and to identify possible intervening molecular pathways. Methods: We prepared p53 mutant U373 and LN229 glioma cell lines, which varied by phosphatase and tensin homolog (PTEN) mutational status and were used to make U373 stable transfected cells expressing GFP-LC3 protein. After performing cell survival assay after irradiation, the IC50 radiation dose was determined. Dexamethasone dose (10 µM) was determined from the literature and added to the glioma cells 24 hours before the irradiation. The effect of adding dexamethasone was evaluated by cell survival assay or clonogenic assay and cell cycle analysis. Measurement of autophagy was visualized by western blot of LC3-I/LC3-II and quantified by the GFP-LC3 punctuated pattern under fluorescence microscopy and acridine orange staining for acidic vesicle organelles by flow cytometry. Results: Dexamethasone increased cell survival in both U373 and LN229 cells after irradiation. It interfered with autophagy after irradiation differently depending on the PTEN mutational status : the autophagy decreased in U373 (PTEN-mutated) cells but increased in LN229 (PTEN wild-type) cells. Inhibition of protein kinase B (AKT) phosphorylation after irradiation by LY294002 reversed the dexamethasone-induced decrease of autophagy and cell death in U373 cells but provoked no effect on both autophagy and cell survival in LN229 cells. After ATG5 knockdown, radiation-induced autophagy decreased and the effect of dexamethasone also diminished in both cell lines. The diminished autophagy resulted in a partial reversal of dexamethasone protection from cell death after irradiation in U373 cells; however, no significant change was observed in surviving fraction LN229 cells. Conclusion: Dexamethasone increased cell survival in p53 mutated malignant glioma cells and increased autophagy in PTEN-mutant malignant glioma cell but not in PTEN-wildtype cell. The difference of autophagy response could be mediated though the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway.

4.
Cells ; 9(3)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32183406

RESUMO

Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32037787

RESUMO

Two-dimensional (2D) van der Waals (vdW) heterostructures herald new opportunities for conducting fundamental studies of new physical/chemical phenomena and developing diverse nanodevice applications. In particular, vdW heterojunction p-n diodes exhibit great potential as high-performance photodetectors, which play a key role in many optoelectronic applications. Here, we report on 2D MoTe2/MoS2 multilayer semivertical vdW heterojunction p-n diodes and their optoelectronic application in self-powered visible-invisible multiband detection and imaging. Our MoTe2/MoS2 p-n diode exhibits an excellent electrical performance with an ideality factor of less than 1.5 and a high rectification (ON/OFF) ratio of more than 104. In addition, the photodiode exhibits broad spectral photodetection capability over the range from violet (405 nm) to near-infrared (1310 nm) wavelengths and a remarkable linear dynamic range of 130 dB within an optical power density range of 10-5 to 1 W/cm2 in the photovoltaic mode. Together with these favorable static photoresponses and electrical behaviors, very fast photo- and electrical switching behaviors are clearly observed with negligible changes at modulation frequencies greater than 100 kHz. In particular, inspired by the photoswitching results for periodic red (638 nm) and near-infrared (1310 nm) illumination at 100 kHz, we successfully demonstrate a prototype self-powered visible-invisible multiband image sensor based on the MoTe2/MoS2 p-n photodiode as a pixel. Our findings can pave the way for more advanced developments in optoelectronic systems based on 2D vdW heterostructures.

6.
Exp Mol Med ; 52(1): 79-91, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31956271

RESUMO

The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity.

7.
Exp Mol Med ; 51(10): 1-15, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649250

RESUMO

Nogo receptor (NgR) has been shown to inhibit the migration and invasion of human glioma cells. However, little is known regarding the regulatory mechanisms of NgR in glioblastoma multiforme (GBM). In this study, we propose a novel mechanism that regulates the maturation process of NgR through an interaction with vimentin. The inhibition of TGFß1 activity by LY2109761 attenuated the migration/invasion of GBM cells by upregulating cell-surface NgR. Conversely, the treatment of GBM cells with TGFß1 suppressed NgR maturation. We showed that NgR and vimentin interact, which could be a possible mechanism for the suppression of NgR maturation. The knockdown of vimentin suppressed the migration/invasion of GBM cells through the increased maturation of NgR. Finally, TCGA (The Cancer Genome Atlas) analysis also supported the association of NgR and vimentin. The maturation of NgR is regulated by the interaction of vimentin and NgR, which attenuates the invasive activity of GBM, and might be a potential therapeutic target for brain cancer.

8.
Mol Cells ; 42(8): 604-616, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31446747

RESUMO

Phosphoserine phosphatase (PSPH) is one of the key enzymes of the L-serine synthesis pathway. PSPH is reported to affect the progression and survival of several cancers in an L-serine synthesis-independent manner, but the mechanism remains elusive. We demonstrate that PSPH promotes lung cancer progression through a noncanonical L-serine-independent pathway. PSPH was significantly associated with the prognosis of lung cancer patients and regulated the invasion and colony formation of lung cancer cells. Interestingly, L-serine had no effect on the altered invasion and colony formation by PSPH. Upon measuring the phosphatase activity of PSPH on a serine-phosphorylated peptide, we found that PSPH dephosphorylated phospho-serine in peptide sequences. To identify the target proteins of PSPH, we analyzed the protein phosphorylation profile and the PSPH-interacting protein profile using proteomic analyses and found one putative target protein, IRS-1. Immunoprecipitation and immunoblot assays validated a specific interaction between PSPH and IRS1 and the dephosphorylation of phospho-IRS-1 by PSPH in lung cancer cells. We suggest that the specific interaction and dephosphorylation activity of PSPH have novel therapeutic potential for lung cancer treatment, while the metabolic activity of PSPH, as a therapeutic target, is controversial.


Assuntos
Progressão da Doença , Proteínas Substratos do Receptor de Insulina/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Monoéster Fosfórico Hidrolases/metabolismo , Serina/metabolismo , Células A549 , Animais , Humanos , Camundongos , Invasividade Neoplásica , Fosforilação , Transdução de Sinais , Análise de Sobrevida , Ensaio Tumoral de Célula-Tronco
9.
Adv Mater ; 31(37): e1903277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348581

RESUMO

Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at-site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I-NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I-NM@siRNA nanomedicine demonstrates effective at-site siRNA release resulting from tumoral reactive oxygen species (ROS)-triggered sequential destabilization. Furthermore, the utility of 3I-NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I-NM@siRNA nanomedicine with angiopep-2 peptide is enhanced. The targeted Ang-3I-NM@siRNA exhibits superb blood-brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo-like kinase 1 and vascular endothelial growth factor receptor-2, Ang-3I-NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple-interaction stabilization together with inbuilt self-destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.


Assuntos
Terapia Genética , Glioblastoma/terapia , Nanomedicina , Interferência de RNA , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Terapia Combinada , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Camundongos
10.
Arch Pharm Res ; 42(8): 658-671, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243646

RESUMO

Millions of cells in the human body undergo apoptosis not only under normal physiological conditions but also under pathological conditions such as infection or other diseases related to acute tissue injury. Swift apoptotic cell clearance is essential for tissue homeostasis. Defective clearance of dead cells is linked to pathogenesis of diseases such as inflammatory diseases, atherosclerosis, neurological disease, and cancer. Significance of apoptotic cell clearance has been emerging as an interesting field for disease treatment. Efficient apoptotic cell clearance plays an important role in reducing inflammation through the suppression of inappropriate inflammatory responses under healthy and diseased conditions. However, apoptotic cell clearance related to cancer pathogenesis is more complex in tumor microenvironments. Chronic inflammation resulting from the failure of apoptotic cell clearance can contribute to tumor progression. Conversely, tumor cells can exploit the anti-inflammatory effect of apoptotic cell clearance to generate an immunosuppressive tumor microenvironment. In this review, focus is on the current understanding of apoptotic cell clearance in the tumor microenvironment. Furthermore, we discuss how signaling molecules (PtdSer and PtdSer recognition receptor) mediating apoptotic cell clearance are aberrantly expressed in the tumor microenvironment and their current development state as potential therapeutic targets for clinical cancer therapy.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos
11.
World J Surg Oncol ; 17(1): 59, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30917830

RESUMO

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is frequently associated with hydrocephalus, which quickly devastates the performance of the patient. Cerebrospinal fluid (CSF) shunt is a widely accepted treatment of choice, but the clinical outcomes in patients with LMC are not well studied. This study aimed to examine the efficacy of a CSF shunt in patients with LMC. METHODS: Seventy patients with LMC confirmed by cytology or magnetic resonance imaging (MRI) underwent ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt surgery. We retrospectively analyzed the clinical characteristics of patients, symptom improvement after the shunt, rate of complications associated with the surgery, and overall survival. RESULTS: Fifty-five patients had systemic cancer as a preceding disease, including lung cancer (45), breast cancer (6), and others (4). Primary brain tumors were mainly glioma (7) and medulloblastoma (5). Fifty-one patients had VP shunt, and 19 had LP shunt. After surgery, preoperative symptoms "improved" in 35 patients (50%) and were "normalized" in 24 of those patients (34%). Shunt malfunction occurred in eight patients, and infection occurred in eight patients. Seventeen patients underwent revision due to infection, shunt malfunction, or over-drainage. There were no complications associated with peritoneal seeding during a median follow-up of 3.3 months after surgery. The median overall survival was 8.7 months (95% confidence interval, 6.0-11.4) from LMC diagnosis and 4.1 months from shunt surgery. CONCLUSION: VP or LP shunt is effective for patients with hydrocephalus from LMC in terms of symptom improvement and prolonging of overall survival with an acceptable rate of procedure-related complications. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of the National Cancer Center (retrospectively registered, NCC2018-0051 ).


Assuntos
Neoplasias Encefálicas/patologia , Derivações do Líquido Cefalorraquidiano/métodos , Glioma/complicações , Hidrocefalia/cirurgia , Carcinomatose Meníngea/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Derivações do Líquido Cefalorraquidiano/efeitos adversos , Criança , Pré-Escolar , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Glioma/mortalidade , Glioma/secundário , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/mortalidade , Lactente , Imagem por Ressonância Magnética , Masculino , Carcinomatose Meníngea/mortalidade , Carcinomatose Meníngea/secundário , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
12.
Cancer Res ; 79(7): 1369-1382, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683653

RESUMO

Glioblastoma (GBM) cancer stem cells (CSC) are primarily responsible for metastatic dissemination, resistance to therapy, and relapse of GBM, the most common and aggressive brain tumor. Development and maintenance of CSCs require orchestrated metabolic rewiring and metabolic adaptation to a changing microenvironment. Here, we show that cooperative interplay between the mitochondrial chaperone TRAP1 and the major mitochondria deacetylase sirtuin-3 (SIRT3) in glioma stem cells (GSC) increases mitochondrial respiratory capacity and reduces production of reactive oxygen species. This metabolic regulation endowed GSCs with metabolic plasticity, facilitated adaptation to stress (particularly reduced nutrient supply), and maintained "stemness." Inactivation of TRAP1 or SIRT3 compromised their interdependent regulatory mechanisms, leading to metabolic alterations, loss of stemness, and suppression of tumor formation by GSC in vivo. Thus, targeting the metabolic mechanisms regulating interplay between TRAP1 and SIRT3 may provide a novel therapeutic option for intractable patients with GBM. SIGNIFICANCE: Discovery and functional analysis of a TRAP1-SIRT3 complex in glioma stem cells identify potential target proteins for glioblastoma treatment.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/patologia , Estresse Oxidativo , Sirtuína 3/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Feminino , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo
13.
Amino Acids ; 50(11): 1583-1594, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30105541

RESUMO

Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1-139 a.a)-p53 complex to the autophagosome, through TGase 2 (472-687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81-116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53-TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81-116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.


Assuntos
Carcinoma de Células Renais/enzimologia , Proteínas de Ligação ao GTP/metabolismo , Neoplasias Renais/enzimologia , Proteínas de Neoplasias/metabolismo , Transglutaminases/metabolismo , Regulação Alostérica , Carcinoma de Células Renais/tratamento farmacológico , Linhagem Celular Tumoral , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/genética , Células HEK293 , Humanos , Neoplasias Renais/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Domínios Proteicos , Pirazinas/farmacologia , Transglutaminases/antagonistas & inibidores , Transglutaminases/genética
14.
ACS Appl Mater Interfaces ; 10(36): 30623-30630, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30059199

RESUMO

Two-dimensional (2D) transition metal dichalcogenide (TMD) layers exhibit superior optical, electrical, and structural properties unattainable in any traditional materials. Many of these properties are known to be controllable via external mechanical inputs, benefiting from their extremely small thickness coupled with large in-plane strain limits. However, realization of such mechanically driven tunability often demands highly complicated engineering of 2D TMD layer structures, which is difficult to achieve on a large wafer scale in a controlled manner. Herein, we explore centimeter-scale periodically corrugated 2D TMDs, particularly 2D molybdenum disulfide (MoS2), and report their mechanically tunable multifunctionalities. We developed a water-assisted process to homogeneously integrate few layers of 2D MoS2 on three-dimensionally corrugated elastomeric substrates on a large area (>2 cm2). The evolution of electrical, optical, and structural properties in these three-dimensionally corrugated 2D MoS2 layers was systematically studied under controlled tensile stretch. We identified that they present excellent electrical conductivity and photoresponsiveness as well as systematically tunable surface wettability and optical absorbance even under significant mechanical deformation. These novel three-dimensionally structured 2D materials are believed to offer exciting opportunities for large-scale, mechanically deformable devices of various form factors and unprecedented multifunctionalities.

15.
Exp Mol Med ; 50(5): 1-14, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795377

RESUMO

Antibody-drug conjugates (ADCs) can selectively deliver cytotoxic agents to tumor cells and are frequently more potent than naked antibodies. However, optimization of the conjugation process between antibodies and cytotoxic agents and characterization of ADCs are laborious and time-consuming processes. Here, we describe a novel ADC platform using a tetravalent bispecific antibody that simultaneously binds to the tumor-associated antigen and a hapten conjugated to a cytotoxic agent. We selected cotinine as the hapten because it is not present in biological systems and is inert and nontoxic. We prepared an anti-epidermal growth factor receptor (EGFR) × cotinine bispecific antibody and mixed it with an equimolar amount of cotinine-conjugated duocarmycin to form the ADC. This ADC showed significant in vitro and in vivo antitumor activity against EGFR-positive, cetuximab-refractory lung adenocarcinoma cells with KRAS mutations.


Assuntos
Anticorpos Biespecíficos/farmacologia , Cotinina/farmacologia , Indóis/farmacologia , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Anticorpos Biespecíficos/química , Anticorpos Biespecíficos/farmacocinética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cetuximab/farmacologia , Cotinina/química , Cotinina/farmacocinética , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Anticorpos de Cadeia Única/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Oncogene ; 37(24): 3317-3328, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29559744

RESUMO

Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.


Assuntos
Neoplasias Encefálicas/radioterapia , Matriz Extracelular/efeitos da radiação , Glioblastoma/radioterapia , Ácido Hialurônico/metabolismo , Microambiente Tumoral/efeitos da radiação , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Receptores de Hialuronatos/metabolismo , Hialuronan Sintases/genética , Estimativa de Kaplan-Meier , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/genética , NF-kappa B/metabolismo , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Exp Med ; 215(3): 963-983, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29444818

RESUMO

High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing Sox17-deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7-deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.


Assuntos
Vasos Sanguíneos/anormalidades , Glioma/metabolismo , Glioma/patologia , Fatores de Transcrição SOXF/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Proteínas de Ligação ao Cálcio , Regulação para Baixo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Deleção de Genes , Glioma/irrigação sanguínea , Glioma/imunologia , Humanos , Imunidade , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Gradação de Tumores , Prognóstico , Regulação para Cima , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
18.
Cell Signal ; 44: 138-147, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29329782

RESUMO

Lysophosphatidic acid (LPA) has been implicated in the pathology of human ovarian cancer. This phospholipid elicits a wide range of cancer cell responses, such as proliferation, trans-differentiation, migration, and invasion, via various G-protein-coupled LPA receptors (LPARs). Here, we explored the cellular signaling pathway via which LPA induces migration of ovarian cancer cells. LPA induced robust phosphorylation of ezrin/radixin/moesin (ERM) proteins, which are membrane-cytoskeleton linkers, in the ovarian cancer cell line OVCAR-3. Among the LPAR subtypes expressed in these cells, LPA1 and LPA2, but not LPA3, induced phosphorylation of ERM proteins at their C-termini. This phosphorylation was dependent on the Gα12/13/RhoA pathway, but not on the Gαq/Ca2+/PKC or Gαs/adenylate cyclase/PKA pathway. The activated ERM proteins mediated cytoskeletal reorganization and formation of membrane protrusions in OVCAR-3 cells. Importantly, LPA-induced migration of OVCAR-3 cells was completely abolished not only by gene silencing of LPA1 or LPA2, but also by overexpression of a dominant negative ezrin mutant (ezrin-T567A). Taken together, this study demonstrates that the LPA1/LPA2/ERM pathway mediates LPA-induced migration of ovarian cancer cells. These findings may provide a potential therapeutic target to prevent metastatic progression of ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Proteínas do Citoesqueleto/metabolismo , Lisofosfolipídeos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neoplasias Ovarianas/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Fosforilação , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
19.
Cancer Lett ; 414: 181-189, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29154973

RESUMO

Despite expressing high levels of the epidermal growth factor receptor (EGFR), a majority of oral squamous cell carcinoma (OSCC) patients show limited response to cetuximab and ultimately develop drug resistance. However, mechanism underlying cetuximab resistance in OSCC is not clearly understood. Here, using a mouse orthotopic xenograft model of OSCC, we show that bone morphogenic protein-7-phosphorylated Smad-1, -5, -8 (BMP7-p-Smad1/5/8) signaling contributes to cetuximab resistance. Tumor cells isolated from the recurrent cetuximab-resistant xenograft models exhibited low EGFR expression but extremely high levels of p-Smad1/5/8. Treatment with the bone morphogenic protein receptor type 1 (BMPRI) inhibitor, DMH1 significantly reduced cetuximab-resistant OSCC tumor growth, and combined treatment of DMH1 and cetuximab remarkably reduced relapsed tumor growth in vivo. Importantly, p-Smad1/5/8 level was elevated in cetuximab-resistant patients and this correlated with poor prognosis. Collectively, our results indicate that the BMP7-p-Smad1/5/8 signaling is a key pathway to acquired cetuximab resistance, and demonstrate that combination therapy of cetuximab and a BMP signaling inhibitor as potentially a new therapeutic strategy for overcoming acquired resistance to cetuximab in OSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/antagonistas & inibidores , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cetuximab/administração & dosagem , Receptores ErbB/metabolismo , Humanos , Camundongos Nus , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo
20.
J Microbiol Biotechnol ; 28(1): 165-174, 2018 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-29032648

RESUMO

Glioblastoma multiforme is the most lethal malignant brain tumor. Despite many intensive studies, the prognosis of glioblastoma multiforme is currently very poor, with a median overall survival duration of 14 months and 2-year survival rates of less than 10%. Although viral infections have been emphasized as potential cofactors, their influences on pathways that support glioblastoma progression are not known. Some previous studies indicated that human Kaposi's sarcoma-associated herpesvirus (KSHV) was detected in healthy brains, and its microRNA was also detected in glioblastoma patients' plasma. However, a direct link between KSHV infection and glioblastoma is currently not known. In this study, we infected glioblastoma cells and glioma stem-like cells (GSCs) with KSHV to establish an in vitro cell model for KSHV-infected glioblastoma cells and glioma stem-like cells in order to identify virologic outcomes that overlap with markers of aggressive disease. Latently KSHV-infected glioblastoma cells and GSCs were successfully established. Additionally, using these cell models, we found that KSHV infection modulates the proliferation of glioma stem-like cells.


Assuntos
Proliferação de Células , Glioma/virologia , Herpesvirus Humano 8/crescimento & desenvolvimento , Células-Tronco/fisiologia , Células-Tronco/virologia , Células Tumorais Cultivadas/fisiologia , Células Tumorais Cultivadas/virologia , Células Cultivadas , Humanos
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