DEPTOR suppresses the progression of esophageal squamous cell carcinoma and predicts poor prognosis

Abstract

As a naturally occurring inhibitor of mTOR, accumulated evidence has suggested that DEPTOR plays a pivotal role in suppressing the progression of human malignances. However, the function of DEPTOR in the development of esophageal squamous cell carcinoma (ESCC) is still unclear. Here we report that the expression of DEPTOR is significantly reduced in tumor tissues derived from human patients with ESCC, and the downregulation of DEPTOR predicts a poor prognosis of ESCC patients. In addition, we found that the expression of DEPTOR negatively regulates the tumorigenic activities of ESCC cell lines (KYSE150, KYSE510 and KYSE190). Furthermore, ectopic DEPTOR expression caused a significant suppression of the cellular proliferation, migration and invasion of KYSE150 cells, which has the lowest expression level of DEPTOR in the three cell lines. Meanwhile, CRISPR/Cas9 mediated knockout of DEPTOR in KYSE-510 cells significantly promoted cellular proliferation, migration and invasion. In addition, in vivo assays further revealed that tumor growth was significantly inhibited in xenografts with ectopic DEPTOR expression as compared to untreated KYSE150 cells, and was markedly enhanced in DEPTOR knockout KYSE-510 cells. Biochemical studies revealed that overexpression of DEPTOR led to the suppression of AKT/mTOR pathway as evidenced by reduced phosphorylation of AKT, mTOR and downstream SGK1, indicating DEPTOR might control the progression of ESCC through AKT/mTOR signaling pathway. Thus, these findings, for the first time, demonstrated that DEPTOR inhibits the tumorigenesis of ESCC cells and might serve as a potential therapeutic target or prognostic marker for human patients with ESCC.

DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis

“…DEPTOR is an mTORC1 inhibitor [30, 31], which is closely related to cell proliferation, inflammation, obesity, and cancer [32, 33] and directly connected with cardiovascular disease [34, 35]. One study reported that DEPTOR regulates vascular EC activation and contributes to proinflammatory and angiogenic responses in vitro [18].…”

DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways

“…Supporting the present data, the tumor suppressor role of DEPTOR has been reported in several malignancies, including squamous cell carcinoma (SCC). For example, Ji et al reported that DEPTOR functions as a tumor suppressor, which suppresses tumor cell growth of esophageal SCC, and downregulation of DEPTOR expression predicts a poor prognosis (36). Recently, Baldassarri et al reported that DEPTOR is under-expressed in normal and tumor tissues in non-smoking female patients with lung SCC (37).…”

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.…”