DEPTOR has growth suppression activity against pancreatic cancer cells

Abstract

DEPTOR was reported as a naturally occurring inhibitor of mTORC1 and mTORC2. The role of DEPTOR in the growth and survival of pancreatic cancer cells has not previously been determined. Here we report that while DEPTOR shows a cytoplasmic expression in both normal pancreatic acinar and islet cells in a patchy manner, its expression is reduced in PanIN1 and PanIN2 and completely lost in 100 out of 101 pancreatic ductal adenocarcinoma (PDAC) tissues. Ectopic DEPTOR expression in two pancreatic cancer cell lines, Panc-1 and Miapaca-2, caused a significant 1) suppression of anchorage-dependent growth in monolayer culture, particularly under conditions with growth factor deprivation; 2) decreased clonogenic survival, and 3) suppressed anchorage-independent growth in soft agar. These effects are attributable to moderate induction of apoptosis and growth arrest at the S and G2/M phases, in a cell line dependent manner. Furthermore, ectopic DEPTOR expression moderately inhibited mTORC1 activity, as demonstrated by reduced phosphorylation of S6K, S6, and 4E-BP1. Taken together, these data suggest that DEPTOR has a tumor suppressive activity against pancreatic cancer cells, and its loss of expression may contribute to pancreatic tumorigenesis.

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

“…The role of DEPTOR expression in the progression of human malignancies is still controversial; this may be because the regulation of DEPTOR is complicated in different individuals and tissues (28,31), as two opposite results were obtained in the same myeloma cells (31,58). In lung adenocarcinoma, there is still no direct evidence that DEPTOR regulates tumor progression.…”

“…Various mTOR inhibitors have been used in trials for cancer therapeutic (25,26). DEP domain-containing mTOR-interacting protein (DEPTOR), as a naturally occurring inhibitor of mTOR, usually acts as a tumor suppressor by blocking the activation of mTOR to inhibit cell proliferation, invasion, and survival effect of AKT (27,28). However, under certain circumstances, DEPTOR could act as an oncogene by relieving the feedback inhibition of mTOR, activation of mTOR enhances the downstream S6K expression, which could negatively regulate AKT via downregulating expression of IRS-1/2 (27,29).…”

“…Although the potential role of DEPTOR as an oncogene or a tumor suppressor has been investigated in different types of tumors (28,(31)(32)(33), and DEPTOR could inhibit proliferation of lung adenocarcinoma cells (34), it has not been previously tested whether and how DEPTOR plays a role in EGFR-induced tumor progression of lung adenocarcinoma. In this study, we showed that DEPTOR expression is significantly reduced in patients with lung adenocarcinoma and negatively correlated with EGFR expression.…”

Androgen receptor functions as a negative transcriptional regulator of DEPTOR, mTOR inhibitor

“…Various functions of DEPTOR in cancer progression have been reported. Ectopic expression of the DEPTOR gene is known to reduce mTORC1 activity and cell growth in pancreatic cancer cells (Li et al, 2014). Here, we showed that knockdown of DEPTOR mRNA enhanced phosphorylation degree of S6K and protein level of cyclin D1 in prostate cancer LNCaP cells.…”

“…DEPTOR is suggested to be a tumor suppressor due to the inhibitory effect on mTORC1 and mTORC2 pathways. Recently, the post-translational regulation of DEPTOR was reported (Peterson et al, 2009;Li et al, 2014;Zhao et al, 2011;Gao et al, 2011). DEPTOR was phosphorylated by casein kinase 1 alpha, facilitating ubiquitylation by the F box protein SCF (βTrCP) (Duan et al, 2011).…”