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 retarded by coadministration of cisplatin and CES1 inhibition. Our results thus suggest that CES1 is a promising therapeutic target for HCC treatment.

Phenotypic plasticity, spatial niches and cancer-associated fibroblast/mural cell interactions define the human prostate cancer microenvironment

“…1J-K). CAF1 cells displayed the strongest upregulation of carboxylesterase 1 (CES1), an alternatively spliced ER-localized hydrolase that plays a central role in lipid metabolism 27 (Fig. 4G), a finding consistent with their upregulation of adipogenesis (Fig.…”

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

“…They applied conditioned medium from adipocytes and found that adipocytes induced chemoresistance in OVCA cells via arachidonic acid (omega-6 polyunsaturated fatty acid; PUFA) via activation of Akt ( 70 ). PUFAs and their metabolites are agonists of PPARγ ( 71 ) and even small amounts of PUFAs can induce chemoresistance ( 72 , 73 ). PUFAs from astrocytes have been shown to function as an activator of PPARγ to facilitate brain metastasis ( 74 ).…”

Roles of peroxisome proliferator‐activated receptors in hepatocellular carcinoma

“…Cisplatin combined with CES1 inhibitors can effectively slow down the growth of HCC xenografted mice. 123 Additionally, a dual PPARɑ/γ agonist oroxyloside can inhibit the HCC cell proliferation through metabolic transformation. 112 Giri et al 113 reported that saroglitazar, a PPARα/γ dual agonist, could effectively prevent NASH from developing into liver cancer by inhibiting steatosis, fibrosis and inflammation in rodent models.…”

“…The carboxylesterase 1 (CES1)‐PPARα/γ‐SCD axis may participate in the resistance of HCC cells to cisplatin by interfering with lipid signalling pathways. Cisplatin combined with CES1 inhibitors can effectively slow down the growth of HCC xenografted mice 123 . Additionally, a dual PPARɑ/γ agonist oroxyloside can inhibit the HCC cell proliferation through metabolic transformation 112 .…”