Oncotarget

Research Papers:

Radiosensitization and downregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) upon inhibition of mitogen/extracellular signal-regulated kinase (MEK) in malignant melanoma cells

Stefan Eder _, Andreas Lamkowski, Markus Priller, Matthias Port and Konrad Steinestel

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Oncotarget. 2015; 6:17178-17191. https://doi.org/10.18632/oncotarget.3935

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Abstract

Stefan Eder1, Andreas Lamkowski1, Markus Priller1, Matthias Port1, Konrad Steinestel1,2

1Bundeswehr Institute of Radiobiology, Neuherbergstrasse 11, 80937 Munich, Germany

2Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, Domagkstrasse 17, 48149 Muenster, Germany

Correspondence to:

Stefan Eder, e-mail: stefanfriedricheder@bundeswehr.org

Keywords: nRNP K, MEK inhibition, NRAS, radiotherapy, melanoma

Received: January 12, 2015     Accepted: May 09, 2015     Published: May 22, 2015

ABSTRACT

Background: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is an important cofactor in the p53-mediated DNA damage response pathway upon ionizing radiation (IR) and exerts anti-apoptotic effects also independent of p53 pathway activation. Furthermore, hnRNP K is overexpressed in various neoplasms including malignant melanoma (MM). Here, we investigate the role of hnRNP K in the radioresistance of MM cells.

Methods and results: Our results show cytoplasmic expression of hnRNP K in human MM surgical specimens, but not in benign nevi, and a quick dose- and time-dependent upregulation in response to IR accompanied by cytoplasmic redistribution of the protein in the IPC-298 cellular tumor model carrying an activating NRAS mutation (p.Q61L). SiRNA-based knockdown of hnRNP K induced a delayed decline in γH2AX/53BP1-positive DNA repair foci upon IR. Pharmacological interference with MAPK signaling abrogated ERK phosphorylation, diminished cellular hnRNP K levels, impaired γH2AX/53BP1-foci repair and proliferative capability and increased apoptosis comparable to the observed hnRNP K knockdown phenotype in IPC-298 cells.

Conclusion: Our results indicate that pharmacological interference with MAPK signaling increases vulnerability of NRAS-mutant malignant melanoma cells to ionizing radiation along with downregulation of endogenous hnRNP K and point towards a possible use for combined MEK inhibition and localized radiation therapy of MM in the NRAS-mutant setting where BRAF inhibitors offer no clinical benefit.


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