Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma.
We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in lung adenocarcinoma. ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin-like growth factor 1 receptor in part by maintaining the ... caveolae structure as a scaffold protein of cavin-1 and caveolin-1. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell-based FluoPPI assay detecting ROR1-cavin-1 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90?, but not with other HSP90 paralogs, HSP90? or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose- and time-dependent manner through the ubiquitin/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N-glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1-positive lung adenocarcinoma.
Mesh Terms:
Adenocarcinoma of Lung, Antibiotics, Antineoplastic, Benzoquinones, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Gene Knockdown Techniques, HSP90 Heat-Shock Proteins, High-Throughput Screening Assays, Humans, Lactams, Macrocyclic, Lung Neoplasms, Proteasome Endopeptidase Complex, Proteolysis, RNA-Binding Proteins, Receptor Tyrosine Kinase-like Orphan Receptors
Adenocarcinoma of Lung, Antibiotics, Antineoplastic, Benzoquinones, Cell Line, Tumor, Cell Proliferation, Drug Screening Assays, Antitumor, Gene Knockdown Techniques, HSP90 Heat-Shock Proteins, High-Throughput Screening Assays, Humans, Lactams, Macrocyclic, Lung Neoplasms, Proteasome Endopeptidase Complex, Proteolysis, RNA-Binding Proteins, Receptor Tyrosine Kinase-like Orphan Receptors
Cancer Sci
Date: Mar. 01, 2021
PubMed ID: 33370472
View in: Pubmed Google Scholar
Download Curated Data For This Publication
242903
Switch View:
- Interactions 2