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Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods:Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results:Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway. [ABSTRACT FROM AUTHOR]

There have been paradoxical findings regarding the expression of DEP domain-containing mTOR-interacting protein (DEPTOR) and its role in predicting prognosis in esophageal squamous cell carcinoma (ESCC). Here we show that DEPTOR expression was significantly increased in tumor tissues and predicted good survival in early stage ESCC patients but not in advanced stage patients. In vitro，our studies showed that ESCC cell lines could be classified into relatively high and low DEPTOR-expressing subgroups according to esophageal squamous epithelial cell line Het-1A.In our study, different levels of DEPTOR expression absolutely determined the response to chemotherapy. In relatively low-expressing cell lines, DEPTOR increased chemotherapy sensitivity via deactivation of the AKT pathway. In relatively high-expressing cell lines, DEPTOR increased cell survival and chemoresistance by strong feedback activation of the IRS1-PI3K-AKT-survivin pathway that occurred after downregulation of ribosomal protein S6 kinase (S6K). Collectively, our findings highlight the dichotomous nature of DEPTOR functions in modulating chemotherapy sensitivity in different ESCC cells. [ABSTRACT FROM AUTHOR]