Tid1-L inhibits EGFR signaling in lung adenocarcinoma by enhancing EGFR ubiquitinylation and degradation
Journal
Cancer Research
Journal Volume
73
Journal Issue
13
Pages
4009-4019
Date Issued
2013
Author(s)
Chen C.-Y.
Jan C.-I.
Lo J.-F.
Yang S.-C.
Wang W.-L.
Hong T.-M.
Abstract
Tid1 (DNAJA3), a DnaJ cochaperone, may promote degradation of oncogenic kinases. Tid1 has 2 isoforms, Tid1-L and Tid1-S, that may function differently. In this study, we investigated the role of the Tid1 isoforms in regulating EGF receptor (EGFR) signaling and lung cancer progression. We found that both Tid1-L and Tid1-S expressions were reduced in patients with non-small cell lung cancer compared with normal counterparts. Tid1-L expression correlated inversely with EGFR expression. Low Tid1-L/high EGFR expression predicted poor overall survival in patients with lung adenocarcinoma. Tid1-L overexpression in lung cancer cells attenuated EGFR signaling and inhibited cell proliferation, colony formation, and tumor growth in subcutaneous and orthotropic xenograft models. Conversely, depletion of Tid1 restored EGFR signaling and increased cell proliferation and colony formation. Tid1-L, but not Tid1-S, interacted with EGFR/HSP70/HSP90 through the DnaJ domain, counteracting the EGFR regulatory function of HSP90 by causing EGFR ubiquitinylation and proteasomal degradation. Tid1-L inhibited EGFR signaling even more than the HSP90 inhibitor 17-allylaminodemethoxy geldanamycin. We concluded that Tid1-L acted as a tumor suppressor by inhibiting EGFR signaling through interaction with EGFR/HSP70/HSP90 and enhancing EGFR ubiquitinylation and degradation. ? 2013 American Association for Cancer Research.
SDGs
Other Subjects
epidermal growth factor receptor; heat shock protein 70; heat shock protein 90; protein DnaJ; protein Tid1 L; protein Tid1 S; tanespimycin; unclassified drug; adult; animal experiment; animal model; animal tissue; article; cancer cell; cancer cell culture; cancer growth; cancer inhibition; cell proliferation; colony formation; complex formation; controlled study; female; human; human cell; human tissue; immunohistochemistry; lung adenocarcinoma; lung non small cell cancer; major clinical study; male; mouse; nonhuman; overall survival; priority journal; protein degradation; protein domain; protein expression; protein function; protein interaction; reverse transcription polymerase chain reaction; signal transduction; tumor xenograft; ubiquitination; Adenocarcinoma; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Epidermal Growth Factor; Female; Gene Expression; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Multivariate Analysis; Neoplasm Transplantation; Polyubiquitin; Protein Isoforms; Protein Structure, Tertiary; Proteolysis; Receptor, Epidermal Growth Factor; Signal Transduction; Ubiquitination
Type
journal article