Cotte Alexia Karen, Aires Virginie, Fredon Maxime, Limagne Emeric, Derangère Valentin, Thibaudin Marion, Humblin Etienne, Scagliarini Alessandra, de Barros Jean-Paul Pais, Hillon Patrick, Ghiringhelli François, Delmas Dominique
University of Bourgogne-Franche Comté, F-21000, Dijon, France.
INSERM U1231, Lipids, Nutrition, Cancer, F-21000, Dijon, France.
Nat Commun. 2018 Jan 22;9(1):322. doi: 10.1038/s41467-017-02732-5.
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.
脂滴（LD）积累是目前已被充分认识的癌症标志。然而，在化疗条件下，LD积累在结直肠癌（CRC）生物学中的意义尚未完全明确。由于耐药性是治疗成功的主要障碍，我们试图确定LD积累对CRC化疗耐药性的影响。在此我们表明，CRC细胞的LD含量与溶血磷脂酰胆碱酰基转移酶2（LPCAT2）的表达呈正相关，LPCAT2是一种支持磷脂酰胆碱合成的定位于LD的酶。我们还证明，LD积累在体外和体内均能驱动细胞对5-氟尿嘧啶和奥沙利铂治疗产生抗细胞死亡作用。从机制上讲，LD积累会损害半胱天冬酶级联激活和内质网应激反应。值得注意的是，在小鼠肿瘤移植瘤和CRC患者的转移瘤中，脂滴积累与免疫原性细胞死亡减少和CD8 T细胞浸润有关。我们的研究结果共同表明，LPCAT2介导的LD积累是一种可药物靶向的机制，可恢复CRC细胞的敏感性。
