Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance.
Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance.
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溶血磷脂酰胆碱酰基转移酶2介导的脂质液滴生产支持结直肠癌的化学耐药性。
DOI：
10.1038/s41467-017-02732-5
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发表时间：
2018-01-22
影响因子：
16.6
通讯作者：
Delmas D
中科院分区：
文献类型：
--
作者：
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
脂滴（LD）积聚是目前公认的癌症标志。然而，在化疗条件下，LD积累在结直肠癌（CRC）生物学中的意义尚不完全清楚。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化疗耐药性的贡献。在这里，我们表明，大肠癌细胞的LD含量与溶血磷脂酰胆碱酰基转移酶2（LPCAT 2），一个LD本地化的酶支持磷脂酰胆碱合成的表达呈正相关。我们还证明，LD积累驱动细胞死亡抵抗5-氟尿嘧啶和奥沙利铂治疗在体外和体内。在机制上，LD积累损害半胱天冬酶级联激活和ER应激反应。值得注意的是，液滴积聚与小鼠肿瘤移植物和CRC患者的转移性肿瘤中免疫原性细胞死亡和CD 8 + T细胞浸润的减少相关。总的来说，我们的研究结果强调了LPCAT 2介导的LD积累作为恢复CRC细胞敏感性的药物机制。脂滴（LD）积聚与结直肠癌（CRC）复发相关。在这里，作者表明，化疗通过酰基转移酶LPCAT 2诱导LD合成，这反过来又通过阻断化疗诱导的ER应激，在体外和体内通过LD积累促进化疗耐药性。
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. Lipid droplets (LD) accumulation correlates with colorectal cancer (CRC) relapse. Here the authors show that chemotherapy induces LD synthesis via acyltransferase LPCAT2 which, in turn, promotes chemoresistance via LD accumulation both in vitro and in vivo by blocking chemotherapy-induced ER stress.
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