Fiche publication
Date publication
janvier 2018
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DELMAS Dominique
,
Pr GHIRINGHELLI François
,
Pr HILLON Patrick
,
Dr PAIS DE BARROS Jean-Paul
,
Dr AIRES Virginie
,
Dr LIMAGNE Emeric
,
Dr DERANGERE Valentin
,
Dr THIBAUDIN Marion
Tous les auteurs :
Cotte AK, Aires V, Fredon M, Limagne E, Derangère V, Thibaudin M, Humblin E, Scagliarini A, de Barros JP, Hillon P, Ghiringhelli F, Delmas D
Lien Pubmed
Résumé
Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8 T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
Mots clés
1-Acylglycerophosphocholine O-Acyltransferase, metabolism, Animals, CD8-Positive T-Lymphocytes, cytology, Caspases, metabolism, Cell Death, Cell Line, Tumor, Colorectal Neoplasms, metabolism, Drug Resistance, Neoplasm, Female, Fluorouracil, pharmacology, Homeostasis, Humans, Lipids, chemistry, Liver Neoplasms, secondary, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, Neoplasm Transplantation, Organoplatinum Compounds, pharmacology, Phenotype, Phosphatidylcholines, chemistry, Triglycerides, chemistry
Référence
Nat Commun. 2018 01 22;9(1):322
