Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis

Autores
Martínez López, Nuria; Varela Rey, Marta; Fernández Ramos, David; Woodhoo, Ashwin; Vázquez Chantada, Mercedes; Embade, Nieves; Espinosa Hevia, Luis; Bustamante, Francisco Javier; Parada, Luis Antonio; Rodriguez, Manuel S.; Lu, Shelly C.; Mato, José M.; Martínez Chantar, María L.
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION: The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.
Fil: Martínez López, Nuria. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Varela Rey, Marta. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Fernández Ramos, David. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Woodhoo, Ashwin. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Vázquez Chantada, Mercedes. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Embade, Nieves. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Espinosa Hevia, Luis. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Bustamante, Francisco Javier. Universidad del País Vasco. Hospital de Cruces; España
Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina
Fil: Rodriguez, Manuel S.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas. Parque Tecnológico de Bizkaia; España
Fil: Lu, Shelly C.. University of Southern California. Keck School of Medicine. Division of Gastrointestinal and Liver Diseases; Estados Unidos
Fil: Mato, José M.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Martínez Chantar, María L.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Materia
Lkb1-Akt
Hepatocellular Carcinonma
Steatohepatitis
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/16814
Acceder
id CONICETDig_7874f159affeb176219362a659f3c147
oai_identifier_str oai:ri.conicet.gov.ar:11336/16814
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitisMartínez López, NuriaVarela Rey, MartaFernández Ramos, DavidWoodhoo, AshwinVázquez Chantada, MercedesEmbade, NievesEspinosa Hevia, LuisBustamante, Francisco JavierParada, Luis AntonioRodriguez, Manuel S.Lu, Shelly C.Mato, José M.Martínez Chantar, María L.Lkb1-AktHepatocellular CarcinonmaSteatohepatitishttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION: The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.Fil: Martínez López, Nuria. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Varela Rey, Marta. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Fernández Ramos, David. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Woodhoo, Ashwin. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Vázquez Chantada, Mercedes. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Embade, Nieves. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Espinosa Hevia, Luis. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Bustamante, Francisco Javier. Universidad del País Vasco. Hospital de Cruces; EspañaFil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Rodriguez, Manuel S.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas. Parque Tecnológico de Bizkaia; EspañaFil: Lu, Shelly C.. University of Southern California. Keck School of Medicine. Division of Gastrointestinal and Liver Diseases; Estados UnidosFil: Mato, José M.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaFil: Martínez Chantar, María L.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; EspañaJohn Wiley & Sons Inc2010-10-29info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/16814Martínez López, Nuria; Varela Rey, Marta; Fernández Ramos, David; Woodhoo, Ashwin; Vázquez Chantada, Mercedes; et al.; Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis; John Wiley & Sons Inc; Hepatology (baltimore, Md.); 52; 5; 29-10-2010; 1621-16310270-9139enginfo:eu-repo/semantics/altIdentifier/doi/10.1002/hep.23860info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/hep.23860/abstractinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-29T11:22:42Zoai:ri.conicet.gov.ar:11336/16814instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-29 11:22:43.143CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
title Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
spellingShingle Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
Martínez López, Nuria
Lkb1-Akt
Hepatocellular Carcinonma
Steatohepatitis
title_short Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
title_full Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
title_fullStr Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
title_full_unstemmed Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
title_sort Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis
dc.creator.none.fl_str_mv Martínez López, Nuria
Varela Rey, Marta
Fernández Ramos, David
Woodhoo, Ashwin
Vázquez Chantada, Mercedes
Embade, Nieves
Espinosa Hevia, Luis
Bustamante, Francisco Javier
Parada, Luis Antonio
Rodriguez, Manuel S.
Lu, Shelly C.
Mato, José M.
Martínez Chantar, María L.
author Martínez López, Nuria
author_facet Martínez López, Nuria
Varela Rey, Marta
Fernández Ramos, David
Woodhoo, Ashwin
Vázquez Chantada, Mercedes
Embade, Nieves
Espinosa Hevia, Luis
Bustamante, Francisco Javier
Parada, Luis Antonio
Rodriguez, Manuel S.
Lu, Shelly C.
Mato, José M.
Martínez Chantar, María L.
author_role author
author2 Varela Rey, Marta
Fernández Ramos, David
Woodhoo, Ashwin
Vázquez Chantada, Mercedes
Embade, Nieves
Espinosa Hevia, Luis
Bustamante, Francisco Javier
Parada, Luis Antonio
Rodriguez, Manuel S.
Lu, Shelly C.
Mato, José M.
Martínez Chantar, María L.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lkb1-Akt
Hepatocellular Carcinonma
Steatohepatitis
topic Lkb1-Akt
Hepatocellular Carcinonma
Steatohepatitis
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION: The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.
Fil: Martínez López, Nuria. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Varela Rey, Marta. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Fernández Ramos, David. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Woodhoo, Ashwin. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Vázquez Chantada, Mercedes. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Embade, Nieves. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Espinosa Hevia, Luis. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Bustamante, Francisco Javier. Universidad del País Vasco. Hospital de Cruces; España
Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina
Fil: Rodriguez, Manuel S.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas. Parque Tecnológico de Bizkaia; España
Fil: Lu, Shelly C.. University of Southern California. Keck School of Medicine. Division of Gastrointestinal and Liver Diseases; Estados Unidos
Fil: Mato, José M.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
Fil: Martínez Chantar, María L.. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas; España
description LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION: The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies.
publishDate 2010
dc.date.none.fl_str_mv 2010-10-29
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/16814
Martínez López, Nuria; Varela Rey, Marta; Fernández Ramos, David; Woodhoo, Ashwin; Vázquez Chantada, Mercedes; et al.; Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis; John Wiley & Sons Inc; Hepatology (baltimore, Md.); 52; 5; 29-10-2010; 1621-1631
0270-9139
url http://hdl.handle.net/11336/16814
identifier_str_mv Martínez López, Nuria; Varela Rey, Marta; Fernández Ramos, David; Woodhoo, Ashwin; Vázquez Chantada, Mercedes; et al.; Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis; John Wiley & Sons Inc; Hepatology (baltimore, Md.); 52; 5; 29-10-2010; 1621-1631
0270-9139
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1002/hep.23860
info:eu-repo/semantics/altIdentifier/url/http://onlinelibrary.wiley.com/doi/10.1002/hep.23860/abstract
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons Inc
publisher.none.fl_str_mv John Wiley & Sons Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.10058

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