A novel protein encoded by circASK1 ameliorates gefitinib resistance in lung adenocarcinoma by competitively activating ASK1-dependent apoptosis.

Abstract

Acquired resistance to growth factor receptor tyrosine kinase inhibitors limits the therapeutic benefits gained by EGFR-mutant lung adenocarcinoma (LUAD) patients treated with gefitinib. Circular RNAs (circRNAs) are novel noncoding RNAs implicated in the regulation of chemoresistance in malignancies. However, whether circRNAs participate in the development of EGFR-TKI resistance in LUAD remains to be clarified. Here, we report that circASK1 (hsa_circ_0007798) is significantly downregulated in gefitinib-resistant cells and enhances the gefitinib sensitivity of LUAD cells. Mechanistically, we identified a novel protein encoded by circASK1, ASK1-272a.a, which is essential for ASK1/JNK/p38 signaling activation and mediates the chemosensitivity-inducing effect of circASK1 in LUAD. Importantly, this novel isoform competes with ASK1 for binding to Akt1, therefore antagonizing Akt1-induced ASK1 phosphorylation and inactivation, leading to the activation of ASK1-induced apoptosis and alleviating gefitinib resistance. Moreover, increased YTHDF2-mediated endoribonucleolytic cleavage of m6A-modified circASK1 accounts for its downregulation in gefitinib-resistant cells. The clinical data and in vivo model further corroborated the suppressive effect of circASK1 and its encoded protein on gefitinib resistance. Our study provides a novel therapeutic target to overcome gefitinib resistance in LUAD patients.

• Authors: Tingting Wang, Zhenchuan Liu, Yunlang She, Jiajun Deng, Yifan Zhong, Mengmeng Zhao, Shenghui Li, Dong Xie, Xiwen Sun, Xuefei Hu, Chang Chen
• Journal: Cancer letters (Cancer Lett) Vol. 520 Pg. 321-331 (11 01 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 34389432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• RNA, Circular
• RNA-Binding Proteins
• YTHDF2 protein, human
• AKT1 protein, human
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• Gefitinib

Topics

• Adenocarcinoma of Lung (drug therapy, genetics, pathology)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Gefitinib (adverse effects, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Kinase Kinase 5 (genetics)
• Mice
• Protein Kinase Inhibitors (adverse effects, pharmacology)
• Proto-Oncogene Proteins c-akt (genetics)
• RNA, Circular (genetics)
• RNA-Binding Proteins (genetics)
• Xenograft Model Antitumor Assays