Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy.
Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy.
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DOI：
10.1172/jci.insight.163624
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发表时间：
2023-01-24
期刊：
影响因子：
8
通讯作者：
Sun K
中科院分区：
文献类型：
--
作者：
Li G;Li X;Mahmud I;Ysaguirre J;Fekry B;Wang S;Wei B;Eckel-Mahan KL;Lorenzi PL;Lehner R;Sun K
肝细胞癌（HCC）是肝癌最常见的致死形式。除了手术切除和移植，其他治疗方法尚未很好地建立与HCC患者。在这项研究中，我们发现羧酸酯酶1（CES 1）在HCC中以不同水平表达。我们进一步发现，通过药理学和遗传学方法阻断CES 1会导致脂质谱改变，这与线粒体功能受损直接相关。从机制上讲，脂质组学分析表明，脂质信号分子，包括多不饱和脂肪酸（PUFA），激活PPARα/γ，显着减少CES 1抑制。结果，SCD的表达显著下调，SCD是一种参与肿瘤进展和化疗耐药的PPARα/γ靶基因。临床分析表明，CES 1和SCD在HCC中的蛋白水平之间存在强相关性。通过靶向CES 1-PPARα/γ-SCD轴干扰脂质信号传导使肝癌细胞对顺铂治疗敏感。结果，通过联合施用顺铂和CES 1抑制剂，NU/J小鼠中HCC异种移植肿瘤的生长被有效地减缓。因此，我们的研究结果表明，CES 1是一个有前途的治疗肝癌的治疗靶点。
Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, a PPARα/γ target gene involved in tumor progression and chemoresistance, was significantly downregulated. Clinical analysis demonstrated a strong correlation between the protein levels of CES1 and SCD in HCC. Interference with lipid signaling by targeting the CES1-PPARα/γ-SCD axis sensitized HCC cells to cisplatin treatment. As a result, the growth of HCC xenograft tumors in NU/J mice was potently slowed by coadministration of cisplatin and CES1 inhibition. Our results, thus, suggest that CES1 is a promising therapeutic target for HCC treatment.
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影响因子：
12.8
作者：
Kim M;Lee C;Seo DY;Lee H;Horton JD;Park J;Scherer PE
通讯作者：
Scherer PE
DOI：
10.1186/s40880-018-0301-4
发表时间：
2018-05-21
期刊：
Cancer communications (London, England)
影响因子：
--
作者：
Cheng C;Geng F;Cheng X;Guo D
通讯作者：
Guo D
影响因子：
2.9
作者：
Alannan, Malak;Fayyad-Kazan, Hussein;Merched, Aksam
通讯作者：
Merched, Aksam
影响因子：
4.3
作者：
Baenke F;Peck B;Miess H;Schulze A
通讯作者：
Schulze A
影响因子：
4
作者：
Kalavalapalli, Srilaxmi;Bril, Fernando;Cusi, Kenneth
通讯作者：
Cusi, Kenneth