Radiosensitization and downregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K) upon inhibition of mitogen/extracellular signal-regulated kinase (MEK) in malignant melanoma cells
- Oncotarget. 2015 Jul 10;6(19):17178-91. doi: 10.18632/oncotarget.3935.
- 1. Bundeswehr Institute of Radiobiology, 80937 Munich, Germany.
- 2. Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, 48149 Muenster, Germany.
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.
Conclusions: 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.