2. Academic Validation
  3. Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming

Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming

  • J Med Chem. 2022 Jan 13;65(1):460-484. doi: 10.1021/acs.jmedchem.1c01605.
Yuwen Sheng 1 2,  Yuwen Chen 1 3 4,  Zhongqiu Zeng 1 2,  Wenbi Wu 4,  Jing Wang 1,  Yuling Ma 1,  Yuan Lin 1 5,  Jichao Zhang 1,  Yulan Huang 4,  Wenhua Li 1,  Qiyu Zhu 1,  Xiao Wei 1 3,  Suiyan Li 3,  Wisanee Wisanwattana 1 2,  Fu Li 1,  Wanli Liu 6,  Apichart Suksamrarn 7,  Guolin Zhang 1 8,  Wei Jiao 1,  Fei Wang 1 8
Affiliations

Affiliations

  • 1 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 5 Sichuan Xincheng Biological Co., LTD, Chengdu 611731, China.
  • 6 Ministry of Education Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China.
  • 7 Department of Chemistry and Center of Excellent for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand.
  • 8 Xiongan Institute of Innovation, Chinese Academy of Sciences, Hebei 071700, China.
PMID: 34931827 DOI: 10.1021/acs.jmedchem.1c01605
Abstract

Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the Anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.

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