Abstract B04: NPM1: A new downstream effector of PI3K-AKT-mTOR pathway in prostate cancer?

Nucleophosmin NPM1 is a molecular chaperone involved in many aspect of cellular physiology, eg. ribosomal biogenesis and cell cycle regulation. NPM1 is overexpressed in numerous types of solid tumors, including prostate cancer but the underlying molecular mechanisms are largely unknown. Using both cell lines and transgenic mouse models, we show that NPM1 expression is significantly increased in cells where the PI3K-AKT-mTOR pathway is activated through PTEN deletion. This overexpression is reversed when cells are treated with the pharmacological inhibitor of mTOR rapamycin. In accordance, transfection of small interfering RNA (siRNA) directed against mTOR leads to mTOR and NPM1 downregulation in these cells. In vivo, we found that NPM1 is overexpressed in PTEN knock-out murine prostate, and a one week treatment of these mice with rapamycin leads to NPM1 downregulation. Chromatin Immunoprecipitation (ChIP) assays show that mTOR is localized on NPM1 proximal promoter, close to a binding site for the transcription factor Ying-Yang 1 (YY1). mTOR binding on the chromatin seems to be constitutive, since rapamycin treatment did not alter its localization. mTOR could therefore regulates NPM1 expression by phosphorylating others factors involved in NPM1 gene expression, as previously described (Cunningham et al., 2007). We have previously shown that NPM1 overexpression enhance the migration and invasion abilities of prostate cancer cells (Loubeau et al., 2014). Moreover, NPM1 overexpr...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Downstream Effectors Underlying Cancer Progression: Poster Presentations - Proffered Abstracts Source Type: research