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1.
J Biol Chem ; 286(23): 20423-30, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21502324

RESUMO

HMGCS2 (hydroxymethylglutaryl CoA synthase 2), the gene that regulates ketone body production, is barely expressed in cultured cell lines. In this study, we restored HMGCS2 expression and activity in HepG2 cells, thus showing that the wild type enzyme can induce fatty acid ß-oxidation (FAO) and ketogenesis, whereas a catalytically inactive mutant C166A did not generate either process. Peroxisome proliferator-activated receptor (PPAR) α expression also induces fatty acid ß-oxidation and endogenous HMGCS2 expression. Interestingly, PPARα-mediated induction was abolished when HMGCS2 expression was down-regulated by RNAi. These results indicate that HMGCS2 expression is both sufficient and necessary to the control of fatty acid oxidation in these cells. Next, we examined the expression pattern of several PPARα target genes in this now "ketogenic" HepG2 cell line. FGF21 (fibroblast growth factor 21) expression was specifically induced by HMGCS2 activity or by the inclusion of the oxidized form of ketone bodies (acetoacetate) in the culture medium. This effect was blunted by SirT1 (sirtuin 1) RNAi, so we propose a SirT1-dependent mechanism for FGF21 induction by acetoacetate. These data suggest a novel feed-forward mechanism by which HMGCS2 could regulate adaptive metabolic responses during fasting. This mechanism could be physiologically relevant, because fasting-mediated induction of liver FGF21 was dependent on SirT1 activity in vivo.


Assuntos
Ácidos Graxos/metabolismo , Fatores de Crescimento de Fibroblastos/biossíntese , Regulação da Expressão Gênica/fisiologia , Hidroximetilglutaril-CoA Sintase/metabolismo , Substituição de Aminoácidos , Animais , Jejum/fisiologia , Células Hep G2 , Humanos , Hidroximetilglutaril-CoA Sintase/genética , Corpos Cetônicos/genética , Corpos Cetônicos/metabolismo , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Oxirredução , PPAR alfa/genética , PPAR alfa/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
2.
J Cell Physiol ; 227(4): 1358-66, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21604273

RESUMO

NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP.


Assuntos
Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Substância P/antagonistas & inibidores , Anticorpos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lapatinib , Ligantes , Masculino , Neoplasias/patologia , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Quinazolinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/imunologia , Trastuzumab
3.
Mol Cancer ; 9: 161, 2010 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-20573240

RESUMO

BACKGROUND: CD95 is a death receptor controlling not only apoptotic pathways but also activating mechanisms promoting tumor growth. During the acquisition of chemoresistance to oxaliplatin there is a progressive loss of CD95 expression in colon cancer cells and a decreased ability of this receptor to induce cell death. The aim of this study was to characterize some key cellular responses controlled by CD95 signaling in oxaliplatin-resistant colon cancer cells. RESULTS: We show that CD95 triggering results in an increased metastatic ability in resistant cells. Moreover, oxaliplatin treatment itself stimulates cell migration and decreases cell adhesion through CD95 activation, since CD95 expression inhibition by siRNA blocks the promigratory effects of oxaliplatin. These promigratory effects are related to the epithelia-to-mesenchymal transition (EMT) phenomenon, as evidenced by the up-regulation of some transcription factors and mesenchymal markers both in vitro and in vivo. CONCLUSIONS: We conclude that oxaliplatin treatment in cells that have acquired resistance to oxaliplatin-induced apoptosis results in tumor-promoting effects through the activation of CD95 signaling and by inducing EMT, all these events jointly contributing to a metastatic phenotype.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Receptor fas/metabolismo , Antineoplásicos/farmacologia , Sequência de Bases , Western Blotting , Ciclo Celular , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Citometria de Fluxo , Imunofluorescência , Humanos , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Reação em Cadeia da Polimerase , RNA Interferente Pequeno
4.
J Am Med Dir Assoc ; 21(7): 954-957, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32674827

RESUMO

The COVID-19 pandemic's greatest impact is among older adults. Management of the situation requires a systemic response, and post-acute care (PAC) can provide an adequate mix of active treatment, management of associated geriatric syndromes and palliative care, both in the acute phase, and in post-COVID-19 recovery. In the region of Catalonia, Spain, selected PAC centers have become sites to treat older patients with COVID-19. Referrals come from the emergency department or COVID-19 wards of the acute reference hospitals, nursing homes, or private homes. We critically review the actions taken by Parc Sanitari Pere Virgili, a PAC facility in Barcelona, to manage the pandemic, including its administration, health care, communication, psychological support, and ethical frameworks. We believe that the strategies we used and the lessons we learned can be useful for other sites and countries where similar adaptation of existing facilities may be implemented.


Assuntos
Assistência Integral à Saúde/organização & administração , Infecções por Coronavirus/epidemiologia , Instalações de Saúde/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde , Pneumonia Viral/epidemiologia , Cuidados Semi-Intensivos/organização & administração , Centros de Atenção Terciária/organização & administração , Idoso , COVID-19 , Infecções por Coronavirus/prevenção & controle , Feminino , Geriatria/métodos , Humanos , Masculino , Inovação Organizacional , Pandemias/prevenção & controle , Pandemias/estatística & dados numéricos , Pneumonia Viral/prevenção & controle , Espanha , População Urbana
5.
Mol Cancer Res ; 4(9): 645-53, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16940161

RESUMO

HMGCS2, the gene that regulates ketone body production, is expressed in liver and several extrahepatic tissues, such as the colon. In CaCo-2 colonic epithelial cells, the expression of this gene increases with cell differentiation. Accordingly, immunohistochemistry with specific antibodies shows that HMGCS2 is expressed mainly in differentiated cells of human colonic epithelium. Here, we used a chromatin immunoprecipitation assay to study the molecular mechanism responsible for this expression pattern. The assay revealed that HMGCS2 is a direct target of c-Myc, which represses HMGCS2 transcriptional activity. c-Myc transrepression is mediated by blockade of the transactivating activity of Miz-1, which occurs mainly through a Sp1-binding site in the proximal promoter of the gene. Accordingly, the expression of human HMGCS2 is down-regulated in 90% of Myc-dependent colon and rectum tumors. HMGCS2 protein expression is down-regulated preferentially in moderately and poorly differentiated carcinomas. In addition, it is also down-regulated in 80% of small intestine Myc-independent tumors. Based on these findings, we propose that ketogenesis is an undesirable metabolic characteristic of the proliferating cell, which is down-regulated through c-Myc-mediated repression of the key metabolic gene HMGCS2.


Assuntos
Neoplasias do Colo/genética , Genes myc , Hidroximetilglutaril-CoA Sintase/genética , Acetilação , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Células CACO-2 , Diferenciação Celular/fisiologia , Imunoprecipitação da Cromatina , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Epitélio/patologia , Histona Desacetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Hidroximetilglutaril-CoA Sintase/biossíntese , Imuno-Histoquímica , Corpos Cetônicos/metabolismo , Fatores de Transcrição Kruppel-Like , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição/genética
6.
Cancer Res ; 73(21): 6424-34, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24030979

RESUMO

ERBB receptor transmodulation by heterologous G-protein-coupled receptors (GPCR) generates functional diversity in signal transduction. Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs. In this work, we found that the pain-associated tachykinin Substance P (SP) contributes to persistent transmodulation of the ERBB receptors, EGFR and HER2, in breast cancer, acting to enhance malignancy and therapeutic resistance. SP and its high-affinity receptor NK-1R were highly expressed in HER2(+) primary breast tumors (relative to the luminal and triple-negative subtypes) and were overall correlated with poor prognosis factors. In breast cancer cell lines and primary cultures derived from breast cancer samples, we found that SP could activate HER2. Conversely, RNA interference-mediated attenuation of NK-1R, or its chemical inhibition, or suppression of overall GPCR-mediated signaling, all strongly decreased steady-state expression of EGFR and HER2, establishing that their basal activity relied upon transdirectional activation by GPCR. Thus, SP exposure affected cellular responses to anti-ERBB therapies. Our work reveals an important oncogenic cooperation between NK-1R and HER2, thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored.


Assuntos
Comunicação Autócrina/efeitos dos fármacos , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Substância P/farmacologia , Apoptose , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células , Progressão da Doença , Receptores ErbB/metabolismo , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurotransmissores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Receptores da Neurocinina-1/química , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
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