2-Methoxyestradiol synergizes with Erlotinib to suppress hepatocellular carcinoma by disrupting the PLAGL2-EGFR-HIF-1/2α signaling loop.

Abstract

Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment.

• Authors: Shufang Zheng, Jiaping Ni, Ying Li, Mingying Lu, Yuchen Yao, Haixin Guo, Meng Jiao, Tianle Jin, Haoying Zhang, Ansheng Yuan, Zhuo Wang, Yong Yang, Zhen Chen, Hongxi Wu, Weiwei Hu
• Journal: Pharmacological research (Pharmacol Res) Vol. 169 Pg. 105685 (07 2021) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 34022398 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• PLAGL2 protein, human
• RNA-Binding Proteins
• Transcription Factors
• endothelial PAS domain-containing protein 1
• 2-Methoxyestradiol
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors

Topics

• 2-Methoxyestradiol (administration & dosage, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Cell Line, Tumor
• DNA-Binding Proteins (metabolism)
• Drug Synergism
• ErbB Receptors (metabolism)
• Erlotinib Hydrochloride (administration & dosage, pharmacology, therapeutic use)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Liver Neoplasms (drug therapy, metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Neoplasm Transplantation
• RNA-Binding Proteins (metabolism)
• Signal Transduction (drug effects)
• Transcription Factors (metabolism)
• Mice