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Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells

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Abstract

According to the stem cell theory for cancer, hepatocellular carcinomas are sustained by a group of cancer stem cells (CSCs) which are responsible for resistance to chemotherapy. In the present study we aimed to examine lipid metabolism in cancer stem cells induced by long-term treatment with sorafenib and its relationship with acquisition of a CSC-like phenotype. Two cell lines (HepG2SF1 and Huh7SF1) were generated by incubation with a step-wise increase of sorafenib concentrations for 10 months. These cell lines displayed stem-like characteristics like increase in the expression of ABCB1A, Nanog and Oct4 as well as an E-cadherin/N-cadherin switch. HepG2SF1 and Huh7SF1 cells showed intracellular accumulation of neutral lipids, assessed by flow cytometry and confocal microscopy. The exam of lipid metabolism revealed that HepG2SF1 and Huh7SF1 cells increased the expression of the enzymes involved in de novo lipid synthesis ATP–citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) and that of the fatty acid transporter CD36. In addition, these CSC-like cells had enhanced expression of the lipogenic transcription factor SREBP1c. Analysis of the key metabolic sensor AMP-activated kinase (AMPK) demonstrated that both AMPK phosphorylation and levels were decreased in the CSC-like cells compared to their parental cells. Interestingly, transfection of HepG2SF1 and Huh7SF1 cells with AMPK, restored the levels of the lipogenic enzymes and SREBP1c and decreased the intracellular lipid accumulation. Furthermore, AMPK transfection decreased the stemness markers and inhibited the E-cadherin/N-cadherin switch. Targeting AMPK and lipid metabolism of hepatocellular cancer stem cells is a promising strategy to face stemness and chemotherapy resistance.

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Acknowledgements

The authors would like to thank Fundación Tatiana Pérez de Guzmán el Bueno (Grant Nº Patrocinio 2019-001) for financial support into their research. Authors acknowledge Dr. G. Hardie for providing AMPK plasmids.

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Authors and Affiliations

  1. Biochemistry and Molecular Biology Unit, Department of System Biology, School of Medicine and Health Sciences, University of Alcalá, Ctra A-2, Km 32, 28871, Alcalá de Henares, Madrid, Spain

    Alicia Bort, Belén G. Sánchez, Irene de Miguel, Pedro A. Mateos-Gómez & Inés Diaz-Laviada

  2. Chemical Research Institute “Andrés M. del Río” (IQAR), Alcalá University, 28871, Alcalá de Henares, Madrid, Spain

    Inés Diaz-Laviada

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  1. Alicia Bort
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  2. Belén G. Sánchez
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IDL conceived and supervised the study; AB and IDL designed experiments; BS, IdeM and AB performed experiments; BS and PMG analyzed data; IDL wrote the manuscript.

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Correspondence to Inés Diaz-Laviada.

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Bort, A., Sánchez, B.G., de Miguel, I. et al. Dysregulated lipid metabolism in hepatocellular carcinoma cancer stem cells. Mol Biol Rep 47, 2635–2647 (2020). https://doi.org/10.1007/s11033-020-05352-3

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