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1.
Br J Cancer ; 129(8): 1350-1361, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37673961

RESUMO

BACKGROUND: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. METHODS: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). RESULTS: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. CONCLUSION: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Camundongos , Animais , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Linhagem Celular Tumoral , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Nitrilas/farmacologia , RNA Interferente Pequeno/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Proliferação de Células
2.
Front Oncol ; 12: 982231, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36033439

RESUMO

Receptor for hyaluronic acid-mediated motility (RHAMM) is a cell surface receptor for hyaluronic acid that is critical for cell migration and a cell cycle protein involved in microtubule assembly and stability. These functions of RHAMM are required for cellular stress responses and cell cycle progression but are also exploited by tumor cells for malignant progression and metastasis. RHAMM is often overexpressed in tumors and is an independent adverse prognostic factor for a number of cancers such as breast and prostate. Interestingly, pharmacological or genetic inhibition of RHAMM in vitro and in vivo ablates tumor invasiveness and metastatic spread, implicating RHAMM as a potential therapeutic target to restrict tumor growth and improve patient survival. However, RHAMM's pro-tumor activity is dependent on its subcellular distribution, which complicates the design of RHAMM-directed therapies. An alternative approach is to identify downstream signaling pathways that mediate RHAMM-promoted tumor aggressiveness. Herein, we discuss the pro-tumoral roles of RHAMM and elucidate the corresponding regulators and signaling pathways mediating RHAMM downstream events, with a specific focus on strategies to target the RHAMM signaling network in cancer cells.

3.
Elife ; 102021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382934

RESUMO

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular , Emodina/análogos & derivados , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Via de Pentose Fosfato , Neoplasias da Próstata/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
4.
Metabolism ; 82: 88-99, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29366755

RESUMO

BACKGROUND: Chronic progression of diabetes is associated with decreased pancreatic islet mass due to apoptosis of ß-cells. Patients with diabetes have increased circulating matrix metalloproteinase-2 (MMP2); however, the physiological significance has remained elusive. This study tested the hypothesis that MMP2 inhibits cell apoptosis, including islet ß-cells. METHODS: Samples from diabetic patients and newly developed transgenic mice overexpressing human MMP2 (hMMP2) were harnessed, and diabetes was induced with streptozotocin. RESULTS: Circulating hMMP2 was significantly increased in diabetic patients compared to controls and significantly correlated with the serum C-peptide levels. The diabetic hMMP2 transgenic mice showed significant improvements in glycemia, glucose tolerance and insulin secretion compared to diabetic wild type mice. Importantly, the increased hMMP2 levels in mice correlated with significant reduction in islet ß-cell apoptosis compared to wild-type counterparts, and an inhibitor of hMMP2 reversed this mitigating activity against diabetes. The increased activation of Akt and BAD induced by hMMP2 in ß-cells compared to controls, links this signaling pathway to the anti-apoptotic activity of hMMP2, a property that was reversible by both an hMMP2 inhibitor and antibody against integrin-ß3. CONCLUSION: Overall, this study demonstrates that increased expression of hMMP2 may attenuate the severity of diabetes by protecting islet ß-cells from apoptosis through an integrin-mediated activation of the Akt/BAD pathway.


Assuntos
Apoptose/fisiologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ilhotas Pancreáticas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Adulto , Idoso , Animais , Feminino , Teste de Tolerância a Glucose , Humanos , Integrinas/metabolismo , Masculino , Metaloproteinase 2 da Matriz/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia
5.
Am J Pathol ; 187(10): 2312-2322, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28739343

RESUMO

Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin (rhTM) improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of rhTM in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor-ß1 that develop spontaneously pulmonary fibrosis, and wild-type mice treated with bleomycin were used as models of lung fibrosis. rhTM was administered to mice by i.p. injection or by the intranasal route. Therapy with rhTM significantly decreased the concentration of high mobility group box1, interferon-γ, and fibrinolytic markers, the expression of growth factors including transforming growth factor-ß1, and the degree of lung fibrosis. rhTM significantly suppressed apoptosis of lung epithelial cells in in vivo and in vitro experiments. The results of the present study demonstrated that rhTM can inhibit bleomycin-induced pulmonary fibrosis and transforming growth factor-ß1-driven exacerbation and progression of pulmonary fibrosis, and that apart from its well-recognized anticoagulant and anti-inflammatory properties, rhTM can also suppress apoptosis of lung epithelial cells.


Assuntos
Apoptose , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Trombomodulina/uso terapêutico , Células A549 , Administração Intranasal , Administração Intravenosa , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Apoptose/efeitos dos fármacos , Progressão da Doença , Feminino , Humanos , Injeções Intraperitoneais , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Fibrose Pulmonar/complicações , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Trombomodulina/administração & dosagem , Trombomodulina/sangue , Fator de Crescimento Transformador beta1/metabolismo
7.
Diabetes ; 65(7): 1940-51, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27207541

RESUMO

Protein S is an anticoagulant factor that also regulates inflammation and cell apoptosis. The effect of protein S on diabetes and its complications is unknown. This study compared the development of diabetes between wild-type and transgenic mice overexpressing human protein S and the development of diabetic glomerulosclerosis between mice treated with and without human protein S and between wild-type and protein S transgenic mice. Mice overexpressing protein S showed significant improvements in blood glucose level, glucose tolerance, insulin sensitivity, and insulin secretion compared with wild-type counterparts. Exogenous protein S improved insulin sensitivity in adipocytes, skeletal muscle, and liver cell lines in db/db mice compared with controls. Significant inhibition of apoptosis with increased expression of BIRC3 and Bcl-2 and enhanced activation of Akt/PKB was induced by protein S in islet ß-cells compared with controls. Diabetic wild-type mice treated with protein S and diabetic protein S transgenic mice developed significantly less severe diabetic glomerulosclerosis than controls. Patients with type 2 diabetes had significantly lower circulating free protein S than healthy control subjects. This study shows that protein S attenuates diabetes by inhibiting apoptosis of ß-cells and the development of diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Proteína S/genética , Proteína S/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteína S/metabolismo
8.
J Asthma Allergy ; 8: 29-37, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26005353

RESUMO

BACKGROUND: Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells. MATERIALS AND METHODS: Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells. RESULTS: Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C-treated ovalbumin-pulsed dendritic cells had significantly less airway hyperresponsiveness, significantly decreased lung concentrations of Th1 and Th2 cytokines, and less plasma concentration of immunoglobulin E when compared to control mice. CONCLUSION: These results suggest that dendritic cells mediate the immunosuppressive effect of activated protein C during allergic inflammation.

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