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Published on: May 21, 2019
DEPTOR has growth suppression activity against pancreatic cancer cells
Hua Li1, Grace Y Sun1, Yongchao Zhao1
1Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
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.
Insights
DEPTOR inhibits pancreatic cancer cell growth and survival. Loss of DEPTOR expression is linked to pancreatic ductal adenocarcinoma (PDAC) development, suggesting a tumor suppressive role.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- DEPTOR is a known inhibitor of mTORC1 and mTORC2 signaling pathways.
- The function of DEPTOR in pancreatic cancer has not been previously elucidated.
Purpose of the Study:
- To investigate the role of DEPTOR in pancreatic cancer cell growth and survival.
- To determine the expression pattern of DEPTOR in pancreatic lesions and pancreatic ductal adenocarcinoma (PDAC).
Main Methods:
- Immunohistochemical analysis of DEPTOR expression in normal pancreatic tissues, PanIN lesions, and PDAC.
- Ectopic expression of DEPTOR in pancreatic cancer cell lines (Panc-1, Miapaca-2).
- Assessment of cell proliferation, clonogenic survival, apoptosis, cell cycle, and mTORC1 activity following DEPTOR re-expression.
Main Results:
- DEPTOR expression is reduced in PanINs and lost in most PDAC tissues.
- Ectopic DEPTOR expression suppressed anchorage-dependent and -independent growth, clonogenic survival, and induced apoptosis and cell cycle arrest.
- DEPTOR re-expression moderately inhibited mTORC1 activity, evidenced by decreased phosphorylation of S6K, S6, and 4E-BP1.
Conclusions:
- DEPTOR exhibits tumor suppressive activity in pancreatic cancer cells.
- Loss of DEPTOR expression may be a contributing factor in pancreatic tumorigenesis.
- DEPTOR represents a potential therapeutic target for pancreatic cancer.
