de Gauna, Mikel Ruiz and Biancaniello, Francesca and Gonzalez-Romero, Francisco and Rodrigues, Pedro M. and Lapitz, Ainhoa and Gomez-Santos, Beatriz and Olaizola, Paula and Di Matteo, Sabina and Aurrekoetxea, Igor and Labiano, Ibone and Nieva-Zuluaga, Ane and Benito-Vicente, Asier and Perugorria, Maria J. and Apodaka-Biguri, Maider and Paiva, Nuno A. and de Urturi, Diego Saenz and Buque, Xabier and Delgado, Igotz and Martin, Cesar and Azkargorta, Mikel and Elortza, Felix and Calvisi, Diego F. and Andersen, Jesper B. and Alvaro, Domenico and Cardinale, Vincenzo and Bujanda, Luis and Banales, Jesus M. and Aspichueta, Patricia (2022) Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids. HEPATOLOGY, 76 (6). pp. 1617-1633. ISSN 0270-9139, 1527-3350
Full text not available from this repository. (Request a copy)Abstract
Background and Aims Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation. Approach and Results The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA. Conclusions Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | THERAPEUTIC TARGETS; UP-REGULATION; CANCER; PHOSPHATIDYLCHOLINE; PHOSPHATIDYLETHANOLAMINE; CLASSIFICATION; INHIBITORS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Jan 2024 15:01 |
| Last Modified: | 29 Jan 2024 15:01 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58611 |
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