GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells

Hernández-Rizo, Sharik; Simoni-Nieves, Arturo; Gerardo-Ramírez, Montserrat; Torres, Sandra; Fucho, Raquel; Gonzalez, Jonathan; Castellanos‐Tapia, Lyssia; Hernández‐Pando, Rogelio; Tejero‐Barrera, Elizabeth; Bucio, Leticia; Souza, Verónica; Miranda‐Labra, Roxana; Fernández-Checa, José C.; Marquardt, Jens U.; Gómez-Quiroz, Luís Enrique; García-Ruiz, Carmen; Gutiérrez-Ruiz, María Concepción

GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells

Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor‐suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, sphe...

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Autores:	Hernández-Rizo, Sharik, Simoni-Nieves, Arturo, Gerardo-Ramírez, Montserrat, Torres, Sandra, Fucho, Raquel, Gonzalez, Jonathan, Castellanos‐Tapia, Lyssia, Hernández‐Pando, Rogelio, Tejero‐Barrera, Elizabeth, Bucio, Leticia, Souza, Verónica, Miranda‐Labra, Roxana, Fernández-Checa, José C., Marquardt, Jens U., Gómez-Quiroz, Luís Enrique, García-Ruiz, Carmen, Gutiérrez-Ruiz, María Concepción
Tipo de recurso:	artículo
Estado:	Versión aceptada para publicación
Fecha de publicación:	2021
País:	España
Institución:	Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/230389
Acceso en línea:	http://hdl.handle.net/10261/230389
Access Level:	acceso abierto
Palabra clave:	Cholesterol GDF11 HCC Huh7 cells Metabolism Mitochondria

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network_name_str	España
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dc.title.none.fl_str_mv	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
title	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
spellingShingle	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells Hernández-Rizo, Sharik Cholesterol GDF11 HCC Huh7 cells Metabolism Mitochondria
title_short	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
title_full	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
title_fullStr	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
title_full_unstemmed	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
title_sort	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
dc.creator.none.fl_str_mv	Hernández-Rizo, Sharik Simoni-Nieves, Arturo Gerardo-Ramírez, Montserrat Torres, Sandra Fucho, Raquel Gonzalez, Jonathan Castellanos‐Tapia, Lyssia Hernández‐Pando, Rogelio Tejero‐Barrera, Elizabeth Bucio, Leticia Souza, Verónica Miranda‐Labra, Roxana Fernández-Checa, José C. Marquardt, Jens U. Gómez-Quiroz, Luís Enrique García-Ruiz, Carmen Gutiérrez-Ruiz, María Concepción
author	Hernández-Rizo, Sharik
author_facet	Hernández-Rizo, Sharik Simoni-Nieves, Arturo Gerardo-Ramírez, Montserrat Torres, Sandra Fucho, Raquel Gonzalez, Jonathan Castellanos‐Tapia, Lyssia Hernández‐Pando, Rogelio Tejero‐Barrera, Elizabeth Bucio, Leticia Souza, Verónica Miranda‐Labra, Roxana Fernández-Checa, José C. Marquardt, Jens U. Gómez-Quiroz, Luís Enrique García-Ruiz, Carmen Gutiérrez-Ruiz, María Concepción
author_role	author
author2	Simoni-Nieves, Arturo Gerardo-Ramírez, Montserrat Torres, Sandra Fucho, Raquel Gonzalez, Jonathan Castellanos‐Tapia, Lyssia Hernández‐Pando, Rogelio Tejero‐Barrera, Elizabeth Bucio, Leticia Souza, Verónica Miranda‐Labra, Roxana Fernández-Checa, José C. Marquardt, Jens U. Gómez-Quiroz, Luís Enrique García-Ruiz, Carmen Gutiérrez-Ruiz, María Concepción
author2_role	author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Consejo Nacional de Ciencia y Tecnología (México) Universidad Autónoma Metropolitana (México) Ministerio de Ciencia, Innovación y Universidades (España) Agencia Estatal de Investigación (España) Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España) National Institute on Alcohol Abuse and Alcoholism (US) National Institutes of Health (US) Generalitat de Catalunya European Cooperation in Science and Technology Fundación BBVA Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España) Fundació La Marató de TV3 Gómez-Quiroz, Luís Enrique [0000-0002-5704-5985] Gutiérrez-Ruiz, María Concepción [0000-0003-0501-7226] Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Cholesterol GDF11 HCC Huh7 cells Metabolism Mitochondria
topic	Cholesterol GDF11 HCC Huh7 cells Metabolism Mitochondria
description	Growth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor‐suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor‐suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma‐derived cell lines were exposed to GDF11 (50 ng/ml), RNA‐seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum‐related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real‐time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.
publishDate	2021
dc.date.none.fl_str_mv	2021 2021 2021
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Postprint info:eu-repo/semantics/acceptedVersion
format	article
status_str	acceptedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/230389
url	http://hdl.handle.net/10261/230389
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111669RB PID2019-111669RB/AEI/10.13039/501100011033 info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-85877R SAF2017-85877R/AEI/10.13039/501100011033 https://doi.org/10.1002/jcp.30151 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	Wiley-Liss
publisher.none.fl_str_mv	Wiley-Liss
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling	GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cellsHernández-Rizo, SharikSimoni-Nieves, ArturoGerardo-Ramírez, MontserratTorres, SandraFucho, RaquelGonzalez, JonathanCastellanos‐Tapia, LyssiaHernández‐Pando, RogelioTejero‐Barrera, ElizabethBucio, LeticiaSouza, VerónicaMiranda‐Labra, RoxanaFernández-Checa, José C.Marquardt, Jens U.Gómez-Quiroz, Luís EnriqueGarcía-Ruiz, CarmenGutiérrez-Ruiz, María ConcepciónCholesterolGDF11HCCHuh7 cellsMetabolismMitochondriaGrowth differentiation factor 11 (GDF11) has been characterized as a key regulator of differentiation in cells that retain stemness features. Recently, it has been reported that GDF11 exerts tumor‐suppressive properties in hepatocellular carcinoma cells, decreasing clonogenicity, proliferation, spheroid formation, and cellular function, all associated with a decrement in stemness features, resulting in mesenchymal to epithelial transition and loss of aggressiveness. The aim of the present work was to investigate the mechanism associated with the tumor‐suppressive properties displayed by GDF11 in liver cancer cells. Hepatocellular carcinoma‐derived cell lines were exposed to GDF11 (50 ng/ml), RNA‐seq analysis in Huh7 cell line revealed that GDF11 exerted profound transcriptomic impact, which involved regulation of cholesterol metabolic process, steroid metabolic process as well as key signaling pathways, resembling endoplasmic reticulum‐related functions. Cholesterol and triglycerides determination in Huh7 and Hep3B cells treated with GDF11 exhibited a significant decrement in the content of these lipids. The mTOR signaling pathway was downregulated, and this was associated with a reduction in key proteins involved in the mevalonate pathway. In addition, real‐time metabolism assessed by Seahorse technology showed abridged glycolysis as well as glycolytic capacity, closely related to an impaired oxygen consumption rate and decrement in adenosine triphosphate production. Finally, transmission electron microscopy revealed mitochondrial abnormalities, such as cristae disarrangement, consistent with metabolic changes. Results provide evidence that GDF11 impairs cancer cell metabolism targeting lipid homeostasis, glycolysis, and mitochondria function and morphology.This study was partially funded by a grant from the Consejo Nacionalde Ciencia y Tecnología (CONACYT): CB252942, Fronteras de laCiencia1320, Apoyo al Fortalecimiento y Desarrollo de la Infra-estructura 2013205941 and 2017280788, and Universidad Autonoma Metropolitana. We thank the confocal core unit of the Universidad Autonoma Metropolitana Iztapalapa. SH, MGR, ASN arescholarship holders from Conacyt. We acknowledge the support fromgrants: PID2019111669RB, and SAF201785877R from PlanNacional de IþD, Spain, and by the CIBEREHD; the center grantP50AA011999 Southern California Research Center for ALPD andCirrhosis funded by the National Institute on Alcohol Abuse andAlcoholism/National Institutes of Health (NIH); as well as supportfrom AGAUR of the Generalitat de Catalunya SGR20171112,European Cooperation in Science & Technology (COST) ACTIONCA17112 Prospective European DrugInduced Liver Injury Network,and the Fundación BBVA. RED Nacional 2018102799Tdeenfermedades metabólicas y Cáncer y Proyecto 201916/31 DeFundacion Marató TV3Peer reviewedWiley-LissConsejo Nacional de Ciencia y Tecnología (México)Universidad Autónoma Metropolitana (México)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)National Institute on Alcohol Abuse and Alcoholism (US)National Institutes of Health (US)Generalitat de CatalunyaEuropean Cooperation in Science and TechnologyFundación BBVACentro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (España)Fundació La Marató de TV3Gómez-Quiroz, Luís Enrique [0000-0002-5704-5985]Gutiérrez-Ruiz, María Concepción [0000-0003-0501-7226]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/230389reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111669RBPID2019-111669RB/AEI/10.13039/501100011033info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/SAF2017-85877RSAF2017-85877R/AEI/10.13039/501100011033https://doi.org/10.1002/jcp.30151Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2303892026-05-22T06:33:51Z
score	15,811543

GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells

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