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AICAR and Compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro

Böttcher, K; Longato, L; Marrone, G; Mazza, G; Ghemtio, L; Hall, A; Luong, TV; ... Rombouts, K; + view all (2021) AICAR and Compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro. American Journal of Physiology 10.1152/ajpgi.00262.2020. (In press).

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Abstract

Tumour stroma and microenvironment have been shown to affect hepatocellular carcinoma (HCC) growth, with activated hepatic stellate cells (HSC) as a major contributor in this process. Recent evidence suggests that the energy sensor adenosine monophosphate-activated kinase (AMPK) may mediate a series of essential processes during carcinogenesis and HCC progression. Here, we investigated the effect of different HCC cell lines with known TP53 or CTNBB1 mutations on primary human HSC activation, proliferation and AMPK activation. We show that conditioned media obtained from multiple HCC cell lines differently modulate human hHSC proliferation and hHSC AMPK activity in a paracrine manner. Pharmacological treatment of hHSC with AICAR and Compound C inhibited the HCC-induced proliferation/activation of hHSC through AMPK-dependent and AMPK-independent mechanisms, which was further confirmed using mouse embryonic fibroblasts (MEFs) deficient of both catalytic AMPKα isoforms (AMPKα1/α2-/-) and wild type (wt) MEF. Both compounds induced S-phase cell-cycle arrest and, in addition, AICAR inhibited the mTORC1 pathway by inhibiting phosphorylation of 4E-BP1 and S6 in hHSC and wt MEF. Datamining of the Cancer Genome Atlas (TCGA) and the Liver Cancer (LICA-FR) showed that AMPKα1 (PRKAA1) and AMPKα2 (PRKAA2) expression differed depending on the mutation (TP53 or CTNNB1), tumour grading and G1-G6 classification, reflecting the heterogeneity in human HCC. Overall, we provide evidence that AMPK modulating pharmacological agents negatively modulate HCC-induced hHSC activation and may therefore provide a novel approach to target the mutual, tumour-promoting interactions between hHSC and HCC.

Type: Article
Title: AICAR and Compound C negatively modulate HCC-induced primary human hepatic stellate cell activation in vitro
Location: United States
DOI: 10.1152/ajpgi.00262.2020
Publisher version: https://doi.org/10.1152/ajpgi.00262.2020
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: AMPK, Hepatic Stellate Cells, Hepatocellular carcinoma, TCGA / LICA-FR, tumour-stromal interactions
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Nephrology
URI: https://discovery.ucl.ac.uk/id/eprint/10119577
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