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.

Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth

“…Independent studies have found elevated FOXC2 levels in metastatic 5, 6 and residual therapy-resistant 7 breast tumors, and implicated constitutive p38 signaling in the progression of metaplastic breast cancers 37 , the emergence of therapy-resistance 38–40 , and the tumor-promoting activities of carcinoma-associated fibroblasts 41 . Our data suggest a possible link between FOXC2 elevation and p38 activation in metastasis-prone breast tumors.…”

MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma

“…E2F1, E2F2 and E2F3a are activators of the cell cycle targeting cyclins, CDKs, DNA repair and replication proteins. Furthermore, cyclins, CDK4, CDK6, ETS1, and the G1 cell cycle phase specific transcription factor SP1 are activated by the mitogen-activated protein kinase (MAPK) signaling pathway, targeted by several dysregulated miRs [ 58 ]. The tumor suppressor genes programmed cell death 4 (PDCD4) and phosphatase and tensin homolog (PTEN), also involved in the regulation of cell cycle, are known to be targeted and repressed by miR-21 [ 15 , 59 ].…”

MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

“…In addition to p53 status and tissue-specific roles, the type of the chemotherapeutic agent is also a determinant of MK2 function in chemosensitization [24,48,49]. While MK2 inhibition improved the efficacy of doxorubicin and cisplatin [6,24], MK2 activity is crucial for the efficacy of gemcitabine [48,50]. In support of biased MK2 signaling, MK2 inhibition blocks TNF production in macrophages stimulated with lipopolysaccharide; however, when the same cells were treated with Smac mimetics, MK2 inhibition increased TNF production [9].…”