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

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 4

Blockage of CES1 activity decreases SCD levels through PPARα/γ.

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Blockage of CES1 activity decreases SCD levels through PPARα/γ. (A) IF s...
(A) IF staining of SCD in a human liver tissue array (the same tissue array as in Figure 1A). (B) Pearson’s correlation analysis of CES1 and SCD protein levels in the tissue array (A and Figure 1A). (C) qPCR analysis of SCD levels in HepG2 cells treated with or without 50 μM WWL229 for 48 h (n = 6). (D and E) Western blot analysis and quantification of SCD in the lysates from HepG2 cells treated with or without 50 μM WWL229 for 48 h (n = 3). (F) IF staining of the SCD on HepG2 cells treated with or without 50 μM WWL229 for 48 hours (representative of 6 fields, experiments were repeated 3 times). (G) qPCR analysis of SCD levels in WT and KO HepG2 cells (n = 3). (H and I) Western blot analysis and quantification of SCD and CES1 in lysates from WT and KO HepG2 cells. α-Tubulin was used as the loading control (n = 3). (J) IF staining of SCD on WT and KO HepG2 cells (representative of 6 fields; experiments were repeated 3 times). (K and L) Western blot analysis and quantification of SCD in lysates from WT, KO, and KO with reexpression of CES1 (KO + CES1) in HepG2 cells (n = 3). (M) Dot plot showing the enrichment for lipid ontology. (N) Box plot showing the level of total PUFA (n = 19) in WT, KO, and WWL229-treated HepG2 cells (n = 3). (O) qPCR analysis of SCD levels in different groups of HepG2 cells, including WT, KO, KO with reexpressed CES1 (KO + CES1), and reexpressed CES1 together with siPPARα (KO + CES1 + siPPARα) or siPPARγ (KO + CES1 + siPPARγ) (n = 3). (P and Q) Western blot analysis and quantification of SCD protein levels in different groups of HepG2 cells, including WT, KO, KO with reexpressed CES1 (KO + CES1), and reexpressed CES1 together with siPPARα (KO + CES1 + siPPARα) or siPPARγ (KO + CES1 + siPPARγ) (n = 4). Western blots are the representative of 3 repeats. Each point represents a biological replicate. Data are represented as mean ± SD. Student’s t test for C, E, G, and I. One-way ANOVA followed by Dunnett T3 test for L, N, O, and Q. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.