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1.
Sci Signal ; 8(397): ra98, 2015 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-26443705

RESUMEN

Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1 activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. We found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetically or chemically induced mouse models of CRC, in patient-derived xenografts, and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high-molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (signal transducer and activator of transcription 3; a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viability of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells under hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death, whereas culturing cells under normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Antineoplásicos/farmacología , Neoplasias del Colon/tratamiento farmacológico , Proteínas de Neoplasias/efectos de los fármacos , Fosfoproteínas/antagonistas & inhibidores , Porfirinas/farmacología , Aciltransferasas , Proteínas Adaptadoras Transductoras de Señales/fisiología , Adenocarcinoma/patología , Adenoma/patología , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/patología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Genes APC , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peso Molecular , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Fosfoproteínas/fisiología , Fosforilación , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacos , Procesamiento Proteico-Postraduccional , Factor de Transcripción STAT3/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Verteporfina , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP
2.
J Gastrointest Surg ; 12(2): 288-96, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18049840

RESUMEN

INTRODUCTION: Pancreatic cancer is a deadly cancer with limited sensitivity to gemcitabine. Molecular targeting of critical signaling pathways [nuclear factor kappa-B (NF-kappaB), PI3K/AKT, and mitogen-activated protein kinase (MAPK)] in combination with gemcitabine may improve sensitivity. We hypothesize that pancreatic cancer cell genetics and signaling response to treatment correlate with efficacy of gemcitabine-based molecular targeting strategies. MATERIALS AND METHODS: PANC-1, PaCa-2, and BxPC-3 cells were treated with curcumin, LY294002, or PD325901 alone or in combination with gemcitabine. Proliferation was measured by cell counts and enzyme activity by Western blot and electrophoretic mobility shift assay. RESULTS: Each agent dose-dependently decreased proliferation. All cells decreased NF-kappaB activity with curcumin(24 h) except PaCa-2, MEK activity with PD325901(24 h), and PI3Kinase with LY294002(3 h). However, PI3K rebounded to(PaCa-2) or above (Panc-1,BxPC-3) basal in LY294002-treated cells (24 h). Combinations with gemcitabine resulted in at least additive effects on proliferative inhibition. For PANC-1, curcumin + gemcitabine was nearly synergistic, correlating with gemcitabine-induced NF-kappaB activity. LY294002 + gemcitabine was nearly synergistic in PaCa-2 cells, which showed a lower induction of PI3Kinase activity with LY294002. Finally, gemcitabine + PD325901 was only effective in BxPC-3, which exhibited increased MEK activity with gemcitabine. CONCLUSIONS: These results demonstrate differences in treatment efficacy, which correlate with the cell's signaling response to treatment. Signaling profiles of each tumor may be necessary to determine an optimal chemotherapy for pancreatic cancer.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Antimetabolitos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Cromonas/administración & dosificación , Curcumina/administración & dosificación , Desoxicitidina/análogos & derivados , Inhibidores Enzimáticos/administración & dosificación , Morfolinas/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Western Blotting , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Ensayo de Cambio de Movilidad Electroforética , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/efectos de los fármacos , FN-kappa B/fisiología , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/fisiología , Células Tumorales Cultivadas , Gemcitabina
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