Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Abstract

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 mTORinteracting 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, CK1a, and bTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR 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.

Argininosuccinate Synthase 1-Deficiency Enhances the Cell Sensitivity to Arginine through Decreased DEPTOR Expression in Endometrial Cancer

“…It has been reported that ASS1 knockdown in bladder cancer11 and myxofibrosarcoma10 cell lines and DEPTOR knockout in esophageal squamous cell carcinoma19 and lung adenocarcinoma20 cell lines showed increased cell motility and invasion ability, respectively. These findings suggest that the association between ASS1 and DEPTOR that we found in this study might be applicable to other types of tumor.…”

“…Their kinase activities are negatively regulated by DEPTOR, which is a recently identified mTOR binding protein17. DEPTOR has antitumor activity in pancreatic cancer18, esophageal cancer19, and lung cancer20, whereas DEPTOR promotes the survival of myeloma cells1721 and cervical squamous cell carcinoma cells22. It is known that amino acids, particularly arginine, leucine, and glutamine, activate mTORC1232425.…”

Deptor: not only a mTOR inhibitor

“…At the cellular level, Deptor shows cytoplasmic, mitochondrial and nuclear localizations [7–11]. In this regard, the Deptor nuclear localization has been recently associated with its role in gene transcription regulation in MM cells [8].…”

“…Deptor has been found to play an important role in EGFR (Epidermal Growth Factor Receptor)-induced tumor progression of lung adenocarcinoma and its expression is significantly reduced in patients with this type of pathology [11]. In lung adenocarcinoma where EGFR is overexpressed, low levels of Deptor are observed with a consequent enhanced mTOR kinase activity.…”

“…Furthermore, Deptor downregulation leads to tumor progression and drug resistance. More importantly, upon treatment with gefitinib, an EGFR tyrosine kinase inhibitor, it has been observed an increase in Deptor expression, providing relevant evidence on the importance of Deptor in the development of new therapeutic options [11]. …”