title: The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells.
abstract: Pancreatic carcinoma is the major clinical entity where the nucleoside analog gemcitabine is used for first-line therapy. Overcoming cellular resistance toward gemcitabine remains a major challenge in this context. This raises the need to identify factors that determine gemcitabine sensitivity in pancreatic carcinoma cells. We previously found the MAPK-activated protein kinase 2 (MK2), part of the p38/MK2 stress response pathway, to be required for DNA replication fork stalling when osteosarcoma-derived cells were treated with gemcitabine. As a consequence, inhibition or depletion of MK2 protects these cells from gemcitabine-induced death (Köpper, et al. Proc Natl Acad Sci USA 2013; 110:16856-61). Here, we addressed whether MK2 also determines the sensitivity of pancreatic cancer cells toward gemcitabine. We found that MK2 inhibition reduced the intensity of the DNA damage response and enhanced survival of the pancreatic cancer cell lines BxPC-3, MIA PaCa-2, and Panc-1, which display a moderate to strong sensitivity to gemcitabine. In contrast, MK2 inhibition only weakly attenuated the DNA damage response intensity and did not enhance long-term survival in the gemcitabine-resistant cell line PaTu 8902. Importantly, in BxPC-3 and MIA PaCa-2 cells, inhibition of MK2 also rescued increased H2AX phosphorylation caused by inhibition of the checkpoint kinase Chk1 in the presence of gemcitabine. These results indicate that MK2 mediates gemcitabine efficacy in pancreatic cancer cells that respond to the drug, suggesting that the p38/MK2 pathway represents a determinant of the efficacy by that gemcitabine counteracts pancreatic cancer.
authors.affiliation: Institute of Molecular Oncology; Göttingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Göttingen; Göttingen, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Köpper
authors.affiliation: Institute of Molecular Oncology; Göttingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Göttingen; Göttingen, Germany.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Binkowski
authors.affiliation: Institute of Molecular Oncology; Göttingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Göttingen; Göttingen, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Bierwirth
authors.affiliation: Institute of Molecular Oncology; Göttingen Centre of Molecular Biosciences (GZMB); Faculty of Medicine; University of Göttingen; Göttingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000093542:Gemcitabine; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000964:Antimetabolites, Antineoplastic; D000071877:Checkpoint Kinase 1; D003841:Deoxycytidine; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine; D000099190:MAP-Kinase-Activated Kinase 2; C000605867:CHEK1 protein, human
keywords: Chk1; DNA damage; MAPKAPK2; MK2; chemotherapy; gemcitabine; pancreatic carcinoma