Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma.
MOLECULAR CANCER RESEARCH(2016)
摘要
The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1 alpha, and beta TrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of them TOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth. Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression.
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关键词
lung adenocarcinoma,egfr
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