GDF11 restricts aberrant lipogenesis and changes in mitochondrial structure and function in human hepatocellular carcinoma cells
Por:
Hernandez, Sharik, Simoni-Nieves, Arturo, Gerardo-Ramirez, Monserrat, Torres, Sandra, Fucho, Raquel, Gonzalez, Jonathan, Castellanos-Tapia, Lyssia, Hernandez-Pando, Rogelio, Tejero-Barrera, Elizabeth, Bucio, Leticia, Souza, Veronica, Miranda-Labra, Roxana, Fernandez-Checa, Jose C., Marquardt, Jens U., Gomez-Quiroz, Luis E., Garcia-Ruiz, Carmen, Gutierrez-Ruiz, Maria C.
Publicada:
1 may 2021
Resumen:
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.
Filiaciones:
Univ Autonoma Metropolitana Iztapalapa, Div Ciencias Biol & Salud, Posgrad Biol Expt, Mexico City, DF, Mexico
Univ Autonoma Metropolitana Iztapalapa, Dept Ciencias Salud, Av San Rafael Atlixco 186, Mexico City 09340, DF, Mexico
CSIC, Inst Invest Biomed Barcelona, Dept Cell Death & Proliferat, Liver Unit,Hosp Clin,IDIBAPS, Barcelona, Spain
CIBERehd, Barcelona, Spain
USC, Keck Sch Med, Southern Calif Res Ctr ALPD & Cirrhosis, Los Angeles, CA USA
Inst Nacl Med Genom, Lab Nutrigen, Mexico City, DF, Mexico
INCMNSZ, Dept Patol Expt, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Inst Nacl Cardiol Ignacio Chavez, Inst Invest Biomed, Lab Med Expt,Unidad Med Translac, Mexico City, DF, Mexico
Univ Hosp Schleswig Holstein, Dept Med 1, Lubeck, Germany
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