Abstract
The chaperone nucleophosmin (NPM1) is over-expressed in the epithelial compartment of prostate tumours compared to adjacent healthy epithelium and may represent one of the key actors that support the neoplastic phenotype of prostate adenocarcinoma cells. Yet, the mechanisms that underlie NPM1 mediated phenotype remain elusive in the prostate. To better understand NPM1 functions in prostate cancer cells, we sought to characterize its impact on prostate cancer cells behaviour and decipher the mechanisms by which it may act. Here we show that NPM1 favors prostate tumour cell migration, invasion and colony forming. Furthermore, knockdown of NPM1 leads to a decrease in the growth of LNCaP-derived tumours grafted in Nude mice in vivo. Such oncogenic-like properties are found in conjunction with a positive regulation of NPM1 on the ERK1/2 (Extracellular signal-Regulated Kinases 1/2) kinase phosphorylation in response to EGF (Epidermal Growth Factor) stimulus, which is critical for prostate cancer progression following the setting of an autonomous production of the growth factor. NPM1 could then be a target to switch off specifically ERK1/2 pathway activation in order to decrease or inhibit cancer cell growth and migration.
Highlights
The progression of prostate cancer is associated with alterations of key genes that control the cell homeostasis, their deregulation and/or amplification leading to increased cell proliferation and invasive capacities
We previously identified NPM1 as one of the genes whose expression is significantly increased in prostate tumour cells when compared to non-tumour adjacent tissue [1], indicating that NPM1 could act as an enhancer of prostate cancer progression
These results show that NPM1 is involved in the increase of proliferation and clonogenic capacities of prostate tumour cells
Summary
The progression of prostate cancer is associated with alterations of key genes that control the cell homeostasis, their deregulation and/or amplification leading to increased cell proliferation and invasive capacities. NPM1 has been more recently demonstrated to display chaperone activities It binds to histones, favours DNA-histone assembly, mediates nucleosome formation and relaxes chromatin [3] thereby controlling gene expression. NPM1 interacts with a wide range of maturating proteins to induce their proper folding in the active state. Among those proteins, there are cell growth regulators such as the oncoprotein MDM2 (Mouse Double Minute 2 homolog). We report that the level of NPM1 in prostate cancer cells regulates EGF expression and the MAPK (Mitogen Activated Protein Kinases) signalling pathway. We show that high levels of NPM1 positively impact cell proliferation and cell migration, participating in the control of tumour growth
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