Inhibition of MAPKAPK2/MK2 facilitates DNA replication upon cancer cell treatment with gemcitabine but not cisplatin

被引:10
作者
Li, Yizhu [1 ]
Koepper, Frederik [1 ]
Dobbelstein, Matthias [1 ]
机构
[1] Univ Med Ctr Gottingen, Inst Mol Oncol, Gottingen Ctr Mol Biosci GZMB, D-37077 Gottingen, Germany
关键词
MAPKAPK2; MK2; Gemcitabine; Cisplatin; p38; DNA damage; DNA replication; DNA fiber assays; PROTEIN-KINASE; 2; PANCREATIC-CANCER; OXIDATIVE STRESS; DAMAGE RESPONSE; P38; MAPK; P53; MK2; PHOSPHORYLATION; STABILIZATION; REPAIR;
D O I
10.1016/j.canlet.2018.04.030
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The signaling pathway driven by p38 and MAPKAPK2 alias MK2 is activated as part of stress responses, and these kinases represent attractive drug targets for cancer therapy. However, seemingly conflicting results were obtained when assessing the role of MK2 in chemotherapy. MK2 inhibitors were reported to either enhance or diminish the chemosensitivity of cancer cells. Here we show that this strongly depends on the particular chemotherapeutic drug. Two different MK2 inhibitors increased the proliferating fraction of pancreatic cancer-derived cells upon treatment with gemcitabine, whereas no consistent protection against cisplatin was observed. Both drugs enhanced, rather than attenuated, the toxicity of another DNA crosslinking agent, mitomycin C. Gemcitabine and cisplatin were each capable of activating MK2, and we did not observe differences in the intracellular localization of MK2 upon treatment. However, DNA replication fork progression, as determined by fiber assays, was restored by MK2 inhibition upon treatment with gemcitabine, but not when cisplatin was used. Thus, MK2 is required for the reduction in DNA replication in response to gemcitabine but not to cisplatin. These observations raise the need to carefully evaluate synergisms and antagonisms with conventional chemotherapeutics when taking MK2 inhibitors to the clinics. (C) 2018 Elsevier B.V. All rights reserved.
引用
收藏
页码:45 / 54
页数:10
相关论文
共 36 条
[1]   Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment [J].
Alexandrova, E. M. ;
Yallowitz, A. R. ;
Li, D. ;
Xu, S. ;
Schulz, R. ;
Proia, D. A. ;
Lozano, G. ;
Dobbelstein, M. ;
Moll, U. M. .
NATURE, 2015, 523 (7560) :352-+
[2]   Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2) [J].
Anderson, David R. ;
Meyers, Marvin J. ;
Vernier, William F. ;
Mahoney, Matthew W. ;
Kurumbail, Ravi G. ;
Caspers, Nicole ;
Poda, Gennadiy I. ;
Schindler, John F. ;
Reitz, David B. ;
Mourey, Robert J. .
JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (11) :2647-2654
[3]   An evolutionarily conserved Rit GTPase-p38 MAPK signaling pathway mediates oxidative stress resistance [J].
Cai, Weikang ;
Rudolph, Jennifer L. ;
Harrison, Susan M. W. ;
Jin, Ling ;
Frantz, Aubrey L. ;
Harrison, Douglas A. ;
Andres, Douglas A. .
MOLECULAR BIOLOGY OF THE CELL, 2011, 22 (17) :3231-3241
[4]   p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication [J].
Cannell, Ian G. ;
Kong, Yi W. ;
Johnston, Samantha J. ;
Chen, Melissa L. ;
Collins, Hilary M. ;
Dobbyn, Helen C. ;
Elia, Androulla ;
Kress, Theresia R. ;
Dickens, Martin ;
Clemens, Michael J. ;
Heery, David M. ;
Gaestel, Matthias ;
Eilers, Martin ;
Willis, Anne E. ;
Bushell, Martin .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (12) :5375-5380
[5]   Topoisomerase II Inhibitors and Poisons, and the Influence of Cell Cycle Checkpoints [J].
D'Arcy, Nicholas ;
Gabrielli, Brian .
CURRENT MEDICINAL CHEMISTRY, 2017, 24 (15) :1504-1519
[6]   DNA interstrand crosslink repair and cancer [J].
Deans, Andrew J. ;
West, Stephen C. .
NATURE REVIEWS CANCER, 2011, 11 (07) :467-480
[7]   Phenotype and Genotype of Pancreatic Cancer Cell Lines [J].
Deer, Emily L. ;
Gonzalez-Hernandez, Jessica ;
Coursen, Jill D. ;
Shea, Jill E. ;
Ngatia, Josephat ;
Scaife, Courtney L. ;
Firpo, Matthew A. ;
Mulvihill, Sean J. .
PANCREAS, 2010, 39 (04) :425-435
[8]   A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer [J].
Dietlein, Felix ;
Kalb, Bastian ;
Jokic, Mladen ;
Noll, Elisa M. ;
Strong, Alexander ;
Tharun, Lars ;
Ozretic, Luka ;
Kuenstlinger, Helen ;
Kambartel, Kato ;
Randerath, Winfried J. ;
Juengst, Christian ;
Schmitt, Anna ;
Torgovnick, Alessandro ;
Richters, Andre ;
Rauh, Daniel ;
Siedek, Florian ;
Persigehl, Thorsten ;
Mauch, Cornelia ;
Bartkova, Jirina ;
Bradley, Allan ;
Sprick, Martin R. ;
Trumpp, Andreas ;
Rad, Roland ;
Saur, Dieter ;
Bartek, Jiri ;
Wolf, Juergen ;
Buettner, Reinhard ;
Thomas, Roman K. ;
Reinhardt, H. Christian .
CELL, 2015, 162 (01) :146-159
[9]   Exploiting replicative stress to treat cancer [J].
Dobbelstein, Matthias ;
Sorensen, Claus Storgaard .
NATURE REVIEWS DRUG DISCOVERY, 2015, 14 (06) :405-423
[10]   Targeting tumour-supportive cellular machineries in anticancer drug development [J].
Dobbelstein, Matthias ;
Moll, Ute .
NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (03) :179-196