The small molecule chemical compound cinobufotalin attenuates resistance to DDP by inducing ENKUR expression to suppress MYH9-mediated c-Myc deubiquitination in lung adenocarcinoma.

Abstract

The small molecule chemical compound cinobufotalin (CB) is reported to be a potential antitumour drug that increases cisplatin (DDP) sensitivity in nasopharyngeal carcinoma. In this study, we first found that CB decreased DDP resistance, migration and invasion in lung adenocarcinoma (LUAD). Mechanistic studies showed that CB induced ENKUR expression by suppressing PI3K/AKT signalling to downregulate c-Jun, a negative transcription factor of ENKUR. Furthermore, ENKUR was shown to function as a tumour suppressor by binding to β-catenin to decrease c-Jun expression, thus suppressing MYH9 transcription. Interestingly, MYH9 is a binding protein of ENKUR. The Enkurin domain of ENKUR binds to MYH9, and the Myosin_tail of MYH9 binds to ENKUR. Downregulation of MYH9 reduced the recruitment of the deubiquitinase USP7, leading to increased c-Myc ubiquitination and degradation, decreased c-Myc nuclear translocation, and inactivation of epithelial-mesenchymal transition (EMT) signalling, thus attenuating DDP resistance. Our data demonstrated that CB is a promising antitumour drug and may be a candidate chemotherapeutic drug for LUAD patients.

• Authors: Jia-Hao Liu, Hui-Ling Yang, Shu-Ting Deng, Zhe Hu, Wei-Feng Chen, Wei-Wei Yan, Ren-Tao Hou, Yong-Hao Li, Rui-Ting Xian, Ying-Ying Xie, Yun Su, Li-Yang Wu, Ping Xu, Zhi-Bo Zhu, Xiong Liu, Yu-Ling Deng, Yu-Bing Wang, Zhen Liu, Wei-Yi Fang
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 10 Pg. 2687-2695 (Oct 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 35296779 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Bufanolides
• Calmodulin-Binding Proteins
• ENKUR protein, human
• MYH9 protein, human
• Transcription Factors
• beta Catenin
• Proto-Oncogene Proteins c-akt
• USP7 protein, human
• Ubiquitin-Specific Peptidase 7
• Myosin Heavy Chains
• Myosins
• cinobufotalin
• Cisplatin

Topics

• Adaptor Proteins, Signal Transducing
• Adenocarcinoma of Lung (drug therapy)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bufanolides
• Calmodulin-Binding Proteins
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Myosin Heavy Chains
• Myosins (metabolism)
• Nasopharyngeal Neoplasms (drug therapy)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Transcription Factors (metabolism)
• Ubiquitin-Specific Peptidase 7
• beta Catenin (metabolism)