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  3. Inhibition of abnormally activated HIF-1α-GLUT1/3-glycolysis pathway enhances the sensitivity of hepatocellular carcinoma to 5-caffeoylquinic acid and its derivatives

Inhibition of abnormally activated HIF-1α-GLUT1/3-glycolysis pathway enhances the sensitivity of hepatocellular carcinoma to 5-caffeoylquinic acid and its derivatives

  • Eur J Pharmacol. 2022 Apr 5;920:174844. doi: 10.1016/j.ejphar.2022.174844.
Yilin Pang 1,  Yuanshan Lin 2,  Xueqing Wang 3,  Jing Wang 3,  Qian Liu 3,  Nan Ding 3,  Lin Huang 4,  Qiyu Xiang 5,  Jun Fang 2,  Guoqiang Tan 6,  Jianxin Lyu 7,  Zheng Wang 8
Affiliations

Affiliations

  • 1 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, 410128, China; Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 2 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, 410128, China.
  • 3 Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 4 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.
  • 5 College of Life Science, Nanjing Agricultural University, Nanjing, Jiangsu, 210095, China.
  • 6 Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: tgq@wmu.edu.cn.
  • 7 Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: jxlu313@163.com.
  • 8 College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha, Hunan, 410128, China. Electronic address: zhengw@hunau.edu.cn.
PMID: 35189090 DOI: 10.1016/j.ejphar.2022.174844
Abstract

Over the past few years, the antitumor activity exhibited by 5-caffeylquinic acid (5-CQA), especially its inhibitory effect on hepatocellular carcinoma (HCC) proliferation and metastasis, has been recognized as a new research hotspot. However, impacted by the weak antitumor toxicity of 5-CQA, its clinical application has been limited. In this study, the antitumor effect arising from 5-CQA on HCC cells was evaluated through cell viability assay. In addition, proteomics, flow cytometry, qRT-PCR and western blotting were adopted to investigate the drug resistance mechanism of HCC cells to 5-CQA. As indicated by the results, 5-CQA significantly inhibited the proliferation of HCC cell lines MHCC97H and HCCLM3 with IC5048 h of 546.8 μM and 452 μM, respectively. According to the in-depth studies, the abnormal activation of HIF-1α/glucose transporters/glycolysis pathway of 5-CQA could be a key molecular mechanism leading to drug resistance of HCC cells. Thus, this study found that glucose starvation, glucose analogue 2-DG, Hexokinase Inhibitor bromopyruvic acid and PKM2 inhibitor compound 3k inhibited HCC cell proliferation in synergy with 5-CQA. Furthermore, though the 5-CQA derivatives methyl chlorogenate (MCGA) and 3,5-dicaffeoylquinic acid (3,5-diCQA) exhibited more potent antiproliferation activity in HCC cells than 5-CQA, they also up-regulated the expression of GLUT1/3, whereas they had no effect on hepatocytes. To be specific, under low-glucose culture conditions, the order of sensitivity of HCC cells to CQAs was 3,5-diCQA > MCGA > 5-CQA. In brief, the above results revealed that intervention in glucose metabolism can facilitate the effects of 5-CQA and its derivatives for treating HCC.

Keywords

5-Caffeylquinic acid; Drug resistance; GLUT1; Glycolysis; Hepatocellular carcinoma.

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