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-allylamino-demethoxy 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.
Highlights
Lung cancer is the leading cause of cancer deaths worldwide, and non–small cell lung cancer (NSCLC) is the dominant cell type [1]
Because Tid1 is a DnaJ family protein that may interact with HSP70 through its DnaJ-domain, and because EGF receptor (EGFR) is a client protein of HSP90 [14, 15], we investigated whether the 2 isoforms of Tid1 function as tumor suppressors in lung adenocarcinoma by affecting EGFR signaling through modulation of the EGFR/HSP90/HSP70 complex- and EGFR-dependent pathways
To determine, which isoform of Tid1 is the main tumor suppressor in lung adenocarcinoma, the mRNA levels of splicing variants Tid1-L and Tid1-S were examined by quantitative RT-PCR of 20 surgically resected paired samples of tumor and adjacent normal tissues from patients with NSCLC
Summary
Lung cancer is the leading cause of cancer deaths worldwide, and non–small cell lung cancer (NSCLC) is the dominant cell type [1]. EGF receptor (EGFR), a receptor tyrosine kinase (RTK), is the major driver pathway of lung adenocarcinoma, regulating important tumorigenic processes including proliferation, apoptosis, angiogenesis, and invasion [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Mutated in lung adenocarcinoma [3]; the detailed mechanism of how EGFR signaling regulates oncogenic pathways is unclear. The major signaling pathways activated by EGFR are the mitogen-activated protein kinase, phosphatidylinositol 3kinase–AKT, and the STAT pathways [4]. Ligandinduced kinase activation normally targets EGFR for ubiquitinylation and subsequent degradation in lysosomes [5], several studies have reported that certain EGFR mutants and amplification may escape this regulation [3, 6]
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