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 5

Blockage of CES1 activity induces ROS production and mild ER stress.

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Blockage of CES1 activity induces ROS production and mild ER stress. (A)...
(A) Measurement of cellular ROS production in HepG2 cells treated with or without 50 μM WWL229 for 48 h. ROS were detected with 2’, 7’-dichlorodihydrofluorescein (DCF) by flow cytometry. (B) Quantification of ROS production with geometric values (Gmean) in A (n = 3 per group, each point represents a biological replicate). Data are presented as mean ± SD, Student’s t test (****P < 0.0001). (C) Measurement of cellular ROS production in WT and KO HepG2 cells. ROS were detected with DCF by flow cytometry. (D) Quantification of ROS production with Gmean in C (n = 3 per group, each point represents a biological replicate). Data are presented as mean ± SD, Student’s t test (***P < 0.001). (E) qPCR analysis of antioxidant genes, including SOD1, SOD2, GPX1, and CAT1, in HepG2 cells treated with or without 50 μM WWL229 for 48 hours (n = 3 in each group; each point represents a biological replicate). Data are presented as mean ± SD, Student’s t test (**P < 0.01, ***P < 0.001). (F) qPCR analysis of antioxidant genes, including SOD1, SOD2, GPX1, and CAT1, in the WT, KO, and KO with reexpression of CES1 (KO + CES1) HepG2 cells (n = 3 in each group, each point represents a biological replicate). Data are represented as mean ± SD, 1-way ANOVA followed by Dunnett T3-test (*P < 0.05, versus WT, #P < 0.05 versus KO). (G) Western blot analysis of ER stress–related proteins including BIP, XBP1s, and XBP1u in lysates from HepG2 cells treated with or without 50 μM WWL229 for 48 hours. α-Tubulin was used as the loading control (n = 3 per group; representative of 3 repeats). (H) Quantification of the band intensity in G (n = 3 per group; each point represents a biological replicate). Data are presented as mean ± SD, Student’s t test (*P < 0.05). (I) Western blot analysis of ER stress–related proteins, including BIP, XBP1s, and XBP1u, in lysates from WT and KO HepG2 cells. β-Actin was used as the loading control (n = 3 per group; representative of 3 repeats). (J) Quantification of the band intensity in I (n = 3 per group; each point represents a biological replicate). Data are presented as mean ± SD, Student’s t test (*P < 0.05).