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Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy
Gang Li, … , Richard Lehner, Kai Sun
Gang Li, … , Richard Lehner, Kai Sun
Published December 6, 2022
Citation Information: JCI Insight. 2023;8(2):e163624. https://doi.org/10.1172/jci.insight.163624.
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Research Article Metabolism

Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy

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Abstract

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.

Authors

Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L. Eckel-Mahan, Philip L. Lorenzi, Richard Lehner, Kai Sun

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Figure 1

CES1 is selectively expressed in HCC and is associated with survival among liver cancer patients.

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CES1 is selectively expressed in HCC and is associated with survival amo...
(A) Immunofluorescence (IF) staining of CES1 in human liver tissue array. The array sections contained both normal liver tissues (10 samples at the bottom right in the dashed rectangle) and liver carcinoma samples. (B and C) Analysis of the fluorescence intensity of CES1 staining in A in different groups (***P < 0.001, ****P < 0.0001). (D) Western blot analysis of CES1 expression in HCC cell lines, mouse liver, and healthy human liver tissue. α-Tubulin was used as the loading control (n = 3 per group; representative of 3 repeats). (E) Correlation analysis between the expression levels of CES1 and survival rate among cancer patients from the TCGA PAN-Cancer (PANCAN) database. Data were generated using UCSC Xena with relatively large patient numbers (the numbers were shown in the panel). The cut-off values of the survival curve are the lower and upper quartiles of the CES1 expression; “low” or “high” are the lower and upper quartiles of the CES1 expression, respectively. (F–I) Correlation analysis between the expression levels of CES1 and survival rate among patients with different cancers. Data were generated using a KM plotter (kmplot.com) with relatively large patient numbers (the numbers were shown in each panel). The cut-off values of the survival curve are the lower and upper quartiles of the CES1 expression.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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