Sharik Hernandez, Roxana U. Miranda-Labra, Verónica Souza, Raquel Fucho, Jens U. Marquardt, Rogelio Hernández-Pando, Luis Enrique Gómez-Quiroz, Sandra Torres, Elizabeth Tejero-Barrera, Monserrat Gerardo-Ramírez, José C. Fernández-Checa, Lyssia Castellanos-Tapia, María Concepción Gutiérrez-Ruiz, Leticia Bucio, Jonathan Gonzalez, Carmen García-Ruiz, Arturo Simoni-Nieves, 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, Gutiérrez-Ruiz, María Concepción, Gómez-Quiroz, Luís Enrique [0000-0002-5704-5985], and Gutiérrez-Ruiz, María Concepción [0000-0003-0501-7226]
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., This study was partially funded by a grant from the Consejo Nacionalde Ciencia y Tecnología (CONACYT): CB252942, Fronteras de laCiencia1320, Apoyo al Fortalecimiento y Desarrollo de la Infra-estructura 2013205941 and 2017280788, 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: PID2019111669RB, and SAF201785877R 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 SGR20171112,European Cooperation in Science & Technology (COST) ACTIONCA17112 Prospective European DrugInduced Liver Injury Network,and the Fundación BBVA. RED Nacional 2018102799Tdeenfermedades metabólicas y Cáncer y Proyecto 201916/31 DeFundacion Marató TV3