title: Baseline MAPK signaling activity confers intrinsic radioresistance to KRAS-mutant colorectal carcinoma cells by rapid upregulation of heterogeneous nuclear ribonucleoprotein K (hnRNP K).
abstract: Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is overexpressed in malignant tumors and involved in DNA damage response upon ionizing radiation (IR). Here, we investigate its role in radioresistance of colorectal carcinoma (CRC) and evaluate a pharmacological approach to enhance CRC radiosensitivity via downregulation of hnRNP K. We show that hnRNP K is overexpressed in CRC tissue specimens and upregulated in response to IR in vitro, which occurs faster in KRAS-mutant CRC cells. HnRNP K knockdown impairs cell survival, cell cycle progression and KRAS-dependent radioresistance and increases apoptosis. Using the chicken chorioallantoic membrane assay, a decrease in xenograft tumor growth and radioresistance upon hnRNP K depletion could be verified in vivo, and comparable effects were achieved by suppression of hnRNP K expression using the MEK inhibitor MEK162 (Binimetinib). In summary, KRAS-mutant CRC shows intrinsic radioresistance along with rapid upregulation of hnRNP K in response to IR that can effectively be targeted by MEK inhibition. Our results point towards a possible use of MAPK pathway inhibitors to decrease radioresistance of KRAS-mutant CRC via downregulation of hnRNP K.
authors: Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany. Electronic address: stefanfriedricheder@bundeswehr.org.
authors: Stefan
authors: S
authors: Eder
authors: Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany.
authors: Annette
authors: A
authors: Arndt
authors: Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany.
authors: Andreas
authors: A
authors: Lamkowski
authors: Gerhard Domagk Institute of Pathology, University Hospital Münster, Domagkstrasse 17, 48149 Münster, Germany.
authors: Wassiliki
authors: W
authors: Daskalaki
authors: Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany.
authors: Alexis
authors: A
authors: Rump
authors: Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany.
authors: Markus
authors: M
authors: Priller
authors: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstrasse 20, 89081 Ulm, Germany.
authors: Felicitas
authors: F
authors: Genze
authors: Gerhard Domagk Institute of Pathology, University Hospital Münster, Domagkstrasse 17, 48149 Münster, Germany.
authors: Eva
authors: E
authors: Wardelmann
authors: Bundeswehr Institute of Radiobiology Affiliated to the University of Ulm, Neuherbergstrasse 11, 80937 Munich, Germany.
authors: Matthias
authors: M
authors: Port
authors: Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany; Gerhard Domagk Institute of Pathology, University Hospital Münster, Domagkstrasse 17, 48149 Münster, Germany.
authors: Konrad
authors: K
authors: Steinestel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000235:genetics*; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D034622:RNA Interference; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics*; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D012261:Ribonucleoproteins; C072074:HNRNPK protein, human; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Colorectal carcinoma; Ionizing radiation; KRAS; MEK inhibition; hnRNPK