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

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.

• Authors: Yilin Pang, Yuanshan Lin, Xueqing Wang, Jing Wang, Qian Liu, Nan Ding, Lin Huang, Qiyu Xiang, Jun Fang, Guoqiang Tan, Jianxin Lyu, Zheng Wang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 920 Pg. 174844 (Apr 05 2022) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 35189090 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier B.V.

Chemical References

• Glucose Transporter Type 1
• caffeoylquinic acid
• Quinic Acid

Topics

• Carcinoma, Hepatocellular (pathology)
• Cell Line, Tumor
• Glucose Transporter Type 1 (metabolism)
• Glycolysis
• Humans
• Liver Neoplasms (pathology)
• Quinic Acid (analogs & derivatives)