Interrelated role of Notch signaling and mTORC pathways in prostate cancer cell survival and growth
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Date
2014
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Authors
Nutter, Jennifer Makenzie
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Publisher
East Carolina University
Abstract
Prostate cancer is currently the second highest leading cause of
cancer death in men. Notch is a transmembrane receptor protein that
is part of a signaling pathway necessary in the normal development of
the prostate. Notch1 signaling has been shown to be lost in prostate
adenocarcinoma. One of prostate cancer's biggest risk factors is age
and mTOR has been shown to be linked to longevity and age related
diseases. mTOR exists as two complexes, mTORC 1/2, whose key
functions are to control cell survival, metabolism, and growth.
mTORC1/2 are often overexpressed in cancer. It was also reported that the mTORC1 pathway became inactivated when Notch1 signaling was inhibited in prostate cancer cell line PC-3. Herein, we suggest a link between Notch1 signaling and mTOR pathway activity which led to experiments with DU145 cells manipulated to have decreased Notch1 expression. The data shows that loss of Notch1 signaling causes decreased expression of the mTORC1 component Raptor as well as decreased phosphorylation of mTORC1 downstream target 4E-BP1 in conditions of cell stress. The mTORC2 pathway exhibited decreased phospho-mTOR (Ser2481) in normal conditions and decreased Rictor signaling in both normal and serum starved conditions when Notch1 expression was lost. The data also suggests there is less G[bata]L in conditions of stress in Notch1 knockdown cells. We hypothesize that downregulation of Notch1 signaling leads to the dysfunction of both mTOR pathways.