Phosphoproteome Profiling Reveals Multifunctional Protein NPM1 as part of the Irradiation Response of Tumor Cells

Nadine Wiesmann; Rita Gieringer; Franz Grus; Juergen Brieger

doi:10.1016/j.tranon.2018.10.015

Phosphoproteome Profiling Reveals Multifunctional Protein NPM1 as part of the Irradiation Response of Tumor Cells

Transl Oncol. 2019 Feb;12(2):308-319. doi: 10.1016/j.tranon.2018.10.015. Epub 2018 Nov 16.

Authors

Nadine Wiesmann¹, Rita Gieringer¹, Franz Grus², Juergen Brieger³

Affiliations

¹ Molecular Tumor Biology, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre of the Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
² Experimental Ophthalmology, Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
³ Molecular Tumor Biology, Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Centre of the Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany. Electronic address: brieger@uni-mainz.de.

Abstract

To fight resistances to radiotherapy, the understanding of escape mechanisms of tumor cells is crucial. The aim of this study was to identify phosphoproteins that are regulated upon irradiation. The comparative analysis of the phosphoproteome before and after irradiation brought nucleophosmin (NPM1) into focus as a versatile phosphoprotein that has already been associated with tumorigenesis. We could show that knockdown of NPM1 significantly reduces tumor cell survival after irradiation. NPM1 is dephosphorylated stepwise within 1 hour after irradiation at two of its major phosphorylation sites: threonine-199 and threonine-234/237. This dephosphorylation is not the result of a fast cell cycle arrest, and we found a heterogenous intracellular distribution of NPM1 between the nucleoli, the nucleoplasm, and the cytoplasm after irradiation. We hypothesize that the dephosphorylation of NPM1 at threonine-199 and threonine-234/237 is part of the immediate response to irradiation and of importance for tumor cell survival. These findings could make NPM1 an attractive pharmaceutical target to radiosensitize tumor cells and improve the outcome of radiotherapy by inhibiting the pathways that help tumor cells to escape cell death after gamma irradiation.