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1.
Oncogene ; 34(12): 1532-41, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24704827

RESUMO

Rhabdomyosarcoma (RMS), a neoplasm characterised by undifferentiated myoblasts, is the most common soft tissue tumour of childhood. Although aggressive treatment of RMS could provide long-term benefit, resistance to current therapies is an ongoing problem. We report here that insulin-like growth factor 2-binding protein 1 (IGF2BP1), an oncofetal protein, is expressed in RMS patient-derived cell lines and in primary tumours where it drives translation of the cellular inhibitor of apoptosis 1 (cIAP1), a key regulator of the nuclear factor-κB signalling pathway and of caspase-8-mediated cell death. We demonstrate that reducing the levels of cIAP1 in RMS, either by IGF2BP1 knockdown or by IAP antagonists, sensitises these cells to tumour necrosis factor-α-mediated cell death. Finally, we show that targeting cIAP1 by IAP antagonists delays RMS tumour growth and improve survival in mice. Our results identify IGF2BP1 as a critical translational regulator of cIAP1-mediated apoptotic resistance in RMS and advocate for the combined use of IAP antagonists and tumour necrosis factor-α as a therapeutic approach for this type of cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas Inibidoras de Apoptose/genética , Proteínas de Ligação a RNA/metabolismo , Rabdomiossarcoma/metabolismo , Alcinos/farmacologia , Animais , Apoptose , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Biossíntese de Proteínas , Proteínas de Ligação a RNA/antagonistas & inibidores , Rabdomiossarcoma/tratamento farmacológico , Transdução de Sinais , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligases
2.
Nat Med ; 6(6): 698-702, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10835689

RESUMO

Progression of pulmonary hypertension is associated with increased serine elastase activity and the proteinase-dependent deposition of the extracellular matrix smooth muscle cell survival factor tenascin-C (refs. 1,2). Tenascin-C amplifies the response of smooth muscle cells to growth factors, which are also liberated through matrix proteolysis. Recent organ culture studies using hypertrophied rat pulmonary arteries have shown that elastase inhibitors suppress tenascin-C and induce smooth muscle cell apoptosis. This initiates complete regression of the hypertrophied vessel wall by a coordinated loss of cellularity and extracellular matrix. We now report that elastase inhibitors can reverse advanced pulmonary vascular disease produced in rats by injecting monocrotaline, an endothelial toxin. We began oral administration of the peptidyl trifluoromethylketone serine elastase inhibitors M249314 or ZD0892 21 days after injection of monocrotaline. A 1-week treatment resulted in 92% survival, compared with 39% survival in untreated or vehicle-treated rats. Pulmonary artery pressure and muscularization were reduced by myocyte apoptosis and loss of extracellular matrix, specifically elastin and tenascin-C. After 2 weeks, pulmonary artery pressure and structure normalized, and survival was 86%, compared with 0% in untreated or vehicle-treated rats. Although concomitant treatment with various agents can reduce pulmonary hypertension, we have documented complete regression after establishment of malignant monocrotaline-induced disease.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Elastase Pancreática/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Masculino , Monocrotalina , Elastase Pancreática/metabolismo , Ratos , Ratos Sprague-Dawley
3.
J Clin Invest ; 105(1): 21-34, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10619858

RESUMO

Increased expression of the glycoprotein tenascin-C (TN) is associated with progression of clinical and experimental pulmonary hypertension. In cultured smooth muscle cells (SMCs) TN is induced by matrix metalloproteinases (MMPs) and amplifies the proliferative response to growth factors. Conversely, suppression of TN leads to SMC apoptosis. We now report that hypertrophied rat pulmonary arteries in organ culture, which progressively thicken in association with cell proliferation and matrix accumulation, can be made to regress by inhibiting either serine elastases or MMPs. This effect is associated with reduced TN, suppression of SMC proliferation, and induction of apoptosis. Selective repression of TN by transfecting pulmonary arteries with antisense/ribozyme constructs also induces SMC apoptosis and arrests progressive vascular thickening but fails to induce regression. This failure is related to concomitant expansion of a SMC population, which produces an alternative cell survival alpha(v)beta(3) ligand, osteopontin (OPN), in response to pro-proliferative cues provided by a proteolytic environment. OPN rescues MMP inhibitor-induced SMC apoptosis, and alpha(v)beta(3) blockade induces apoptosis in hypertrophied arteries. Our data suggest that proteinase inhibition is a novel strategy to induce regression of vascular disease because this overcomes the pluripotentiality of SMC-matrix survival interactions and induces coordinated apoptosis and resorption of matrix.


Assuntos
Elementos Antissenso (Genética)/uso terapêutico , Metaloendopeptidases/antagonistas & inibidores , Elastase Pancreática/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Tenascina/antagonistas & inibidores , Doenças Vasculares/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Sequência de Bases , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Masculino , Dados de Sequência Molecular , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Osteopontina , Ratos , Ratos Sprague-Dawley , Sialoglicoproteínas/fisiologia
4.
Circ Res ; 84(10): 1223-33, 1999 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-10347097

RESUMO

Increased elastase activity and deposition of the matrix glycoprotein tenascin-C (TN), codistributing with proliferating smooth muscle cells (SMCs), are features of pulmonary vascular disease. In pulmonary artery (PA) SMC cultures, TN is regulated by matrix metalloproteinases (MMPs) and mechanical stress. On attached collagen gels, MMPs upregulate TN, leading to SMC proliferation, whereas on floating collagen, reduced MMPs suppress TN and induce SMC apoptosis. We now investigate the response of SMCs in the whole vessel by comparing attached and floating conditions using either normal PAs derived from juvenile pigs or normal or hypertrophied rat PAs that were embedded in collagen gels for 8 days. Normal porcine PAs in attached collagen gels were characterized by increasing activity of MMP-2 and MMP-9 assessed by zymography and TN deposition detected by Western immunoblotting and densitometric analysis of immunoreactivity. PAs on floating collagen showed reduced activity of both MMPs and deposition of TN. Tenascin-rich foci were associated with proliferating cell nuclear antigen immunoreactivity, and TN-poor areas with apoptosis, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, but no difference in wall thickness was observed. Although normal rat PAs were similar to piglet vessels, hypertrophied rat PAs showed an amplified response. Increased elastase, MMP-2, TN, and elastin deposition, as well as SMC proliferating cell nuclear antigen positivity, correlated with progressive medial thickening on attached collagen, whereas reduced MMP-2, elastase, TN, and induction of SMC apoptosis accompanied regression of the thickened media on floating collagen. In showing that hypertrophied SMCs in the intact vessel can be made to apoptose and that resorption of extracellular matrix can be achieved by inhibition of elastase and MMPs, our study suggests novel strategies to reverse vascular disease.


Assuntos
Apoptose/fisiologia , Músculo Liso Vascular/patologia , Artéria Pulmonar/patologia , Tenascina/antagonistas & inibidores , Animais , Divisão Celular/fisiologia , Colagenases/metabolismo , Matriz Extracelular/química , Matriz Extracelular/enzimologia , Gelatinases/metabolismo , Expressão Gênica/fisiologia , Hipertrofia , Marcação In Situ das Extremidades Cortadas , Masculino , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Metaloendopeptidases/metabolismo , Músculo Liso Vascular/química , Músculo Liso Vascular/enzimologia , Técnicas de Cultura de Órgãos , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/metabolismo , Artéria Pulmonar/química , Artéria Pulmonar/enzimologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Suínos , Tenascina/genética , Tenascina/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
5.
Am J Pathol ; 150(4): 1349-60, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9094991

RESUMO

Progressive pulmonary hypertension is characterized by smooth muscle cell proliferation and migration leading to occlusive arterial lesions. Previously, using cultured smooth muscle cells, we demonstrated that epidermal growth factor (EGF)-dependent proliferation and migration are dependent on tenascin-C (Tn) and cellular fibronectin (Fn), respectively. In this study we applied immunohistochemistry to lung biopsy tissue from patients with congenital heart defects and pulmonary hypertension to determine how the distribution and intensity of Tn, EGF, proliferating cell nuclear antigen (PCNA), and Fn expression related to arterial abnormalities. With mildly increased wall thickness, minimal Tn, PCNA, and EGF was evident. With progressive hypertrophy, moderately intense foci of Tn were apparent in the adventitia, periendothelium, and occasionally the media but not consistently co-distributing with EGF and PCNA. With obstructive lesions, intense neointimal Tn expression co-localized with EGF and PCNA. Fn accumulation in the periendothelium increased with medial hypertrophy and became more widespread in a diffuse pattern with neointimal formation. The neointima was predominantly composed of alpha-smooth-muscle-actin-positive cells, occasional inflammatory cells with no evidence of apoptosis. These studies are consistent with Tn modulating EGF-dependent neointimal smooth muscle cell proliferation and Fn providing a gradient for smooth muscle cell migration from media to neointima.


Assuntos
Endotélio Vascular/metabolismo , Fibronectinas/análise , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Tenascina/análise , Adolescente , Apoptose , Divisão Celular , Criança , Pré-Escolar , Endotélio Vascular/patologia , Fator de Crescimento Epidérmico/análise , Feminino , Humanos , Lactente , Masculino , Antígeno Nuclear de Célula em Proliferação/análise , Túnica Íntima/metabolismo , Túnica Íntima/patologia , Túnica Média/metabolismo , Túnica Média/patologia
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