TY - JOUR
T1 - Interfering with lipid metabolism through targeting CES1 sensitizes hepatocellular carcinoma for chemotherapy
AU - Li, Gang
AU - Li, Xin
AU - Mahmud, Iqbal
AU - Ysaguirre, Jazmin
AU - Fekry, Baharan
AU - Wang, Shuyue
AU - Wei, Bo
AU - Eckel-Mahan, Kristin L.
AU - Lorenzi, Philip L.
AU - Lehner, Richard
AU - Sun, Kai
N1 - Funding Information:
We thank Zhengmei Mao at the Microscopy Core of the Institute of Molecular Medicine for assistance with imaging and tissue processing and Ville Meretoja from the Flow Cytometry Service Center at the IMM of UTHealth for her technical support on flow cytometry analysis. We further thank Yulin Dai at UTHealth School of Biomedical Informatics for his assistance on bioinformatic analysis. This study was supported by grants from the NIH (R01DK109001, R56DK124419, and R01DK129815 for KS) and the Welsh Foundation Endowment Fund (-7712 for KS). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (University of Texas Health Science Center at Houston) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Publisher Copyright:
© 2023, Li et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2023/1/24
Y1 - 2023/1/24
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.163624
DO - 10.1172/jci.insight.163624
M3 - Article
C2 - 36472914
AN - SCOPUS:85147047040
SN - 2379-3708
VL - 8
JO - JCI Insight
JF - JCI Insight
IS - 2
M1 - e163624
ER -