Targeting positive feedback between BASP1 and EGFR as a therapeutic strategy for lung cancer progression
Journal
Theranostics
Journal Volume
10
Journal Issue
24
Pages
10925-10939
Date Issued
2020
Author(s)
Lin C.-C.
Huang Y.-K.
Cho C.-F.
Lin Y.-S.
Lo C.-C.
Kuo T.-T.
Tseng G.-C.
Cheng W.-C.
Chang W.-C.
Hsiao T.-H.
Liu Y.-H.
Clifford Chao K.S.
Hsu J.L.
Lee P.-C.
Sun X.
Hung M.-C.
Sher Y.-P.
Abstract
Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets. Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1. Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors. Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment. ? The author(s).
SDGs
Other Subjects
arsenic trioxide; brain acid soluble protein 1; epidermal growth factor receptor; membrane protein; proteasome; protein tyrosine kinase; ubiquitin; unclassified drug; antineoplastic agent; arsenic trioxide; BASP1 protein, human; EGFR protein, human; epidermal growth factor receptor; membrane protein; nerve protein; protein kinase inhibitor; repressor protein; animal experiment; animal model; animal tissue; Article; brain metastasis; cancer growth; cancer prognosis; carcinogenicity; cell membrane; controlled study; enzyme assay; human; human cell; human tissue; in vitro study; in vivo study; lung adenocarcinoma; lung cancer; mouse; nonhuman; positive feedback; primary tumor; protein blood level; protein expression; protein localization; protein targeting; proteomics; signal transduction; tumor growth; animal; brain; brain tumor; drug effect; drug resistance; drug screening; gene expression profiling; gene knockdown; genetics; Kaplan Meier method; lung; lung adenocarcinoma; lung tumor; metabolism; mortality; mutation; pathology; physiological feedback; prognosis; protein degradation; tissue microarray; tumor cell line; Adenocarcinoma of Lung; Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Brain; Brain Neoplasms; Cell Line, Tumor; Cell Membrane; Drug Resistance, Neoplasm; ErbB Receptors; Feedback, Physiological; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Kaplan-Meier Estimate; Lung; Lung Neoplasms; Membrane Proteins; Mice; Mutation; Nerve Tissue Proteins; Prognosis; Protein Kinase Inhibitors; Proteolysis; Repressor Proteins; Signal Transduction; Tissue Array Analysis; Xenograft Model Antitumor Assays
Publisher
Ivyspring International Publisher
Type
journal article