2. Academic Validation
  3. Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy

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

  • JCI Insight. 2023 Jan 24;8(2):e163624. doi: 10.1172/jci.insight.163624.
Gang Li 1,  Xin Li 1,  Iqbal Mahmud 2,  Jazmin Ysaguirre 1,  Baharan Fekry 1,  Shuyue Wang 1,  Bo Wei 2,  Kristin L Eckel-Mahan 1 3 4,  Philip L Lorenzi 2,  Richard Lehner 5,  Kai Sun 1 3 4
Affiliations

Affiliations

  • 1 Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • 2 Metabolomic Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 3 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
  • 4 Program in Biochemistry and Cell Biology, MD Anderson Cancer Center-UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.
  • 5 Group on Molecular and Cell Biology of Lipids, Department of Pediatrics, University of Alberta, Alberta, Canada.
PMID: 36472914 DOI: 10.1172/jci.insight.163624
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.

Keywords

Fatty acid oxidation; Metabolism; Signal transduction.

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