Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma.

Abstract

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 HSP90α, but not with other HSP90 paralogs, HSP90β 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.

• Authors: Behnoush Khaledian, Ayumu Taguchi, Kazuo Shin-Ya, Lisa Kondo-Ida, Noritaka Kagaya, Motoshi Suzuki, Taisuke Kajino, Tomoya Yamaguchi, Yukako Shimada, Takashi Takahashi
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 3 Pg. 1225-1234 (Mar 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33370472 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antibiotics, Antineoplastic
• Benzoquinones
• CAVIN1 protein, human
• HSP90 Heat-Shock Proteins
• HSP90AA1 protein, human
• Lactams, Macrocyclic
• RNA-Binding Proteins
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• tanespimycin
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• Proteasome Endopeptidase Complex
• geldanamycin

Topics

• Adenocarcinoma of Lung (drug therapy, pathology)
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Benzoquinones (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Gene Knockdown Techniques
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics, metabolism)
• High-Throughput Screening Assays
• Humans
• Lactams, Macrocyclic (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy, pathology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteolysis (drug effects)
• RNA-Binding Proteins (metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (metabolism)