Interrelated role of Notch signaling and mTORC pathways in prostate cancer cell survival and growth

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.