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

Li, Yizhu; Köpper, Frederik; Dobbelstein, Matthias

doi:10.1016/j.canlet.2018.04.030

Cited by 9 publications

(9 citation statements)

References 35 publications

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“…Furthermore, inhibition of the stromal p38MAPK/MK2 pathway was found to limit breast cancer metastases in mice [32]. These data from others along with our data showing the striking classification of metastasis status among gastric cancer patients by MK2 and its association with a wide range of cytokines suggests pathway blockade is promising for immunotherapy treatment [33].…”

Section: Discussionsupporting

confidence: 73%

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

et al. 2020

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Background: Gastric cancer is associated with chronic inflammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of inflammatory cytokine production that we have been studying in gastrointestinal cancers. Here, we set out to determine the significance of this gene in gastric cancer along with its downstream mediators and if there were differences in the primary tumors with and without metastasis. Methods: Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profile in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal-Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis. Results: The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A significant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1β, IFN-α, MCP-1, IL-1β, IL-6, and TNF-α. Mip-1β was found to have the strongest association with MK2 and metastasis after Sidak correction for multiple testing. Conclusions: MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to differentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1β showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and associated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome.

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Section: Discussionsupporting

confidence: 73%

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

et al. 2020

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“…To solve this problem and effectively inhibit p38MAPK, researchers turned their focus to many of its downstream targets, such as MAPKAPK2. Previous studies have shown that targeting MAPKAPK2 to interdict its downstream events is as good as direct upstream inhibition of the p38MAPK pathway without obvious side effects of p38MAPK inhibitors (38)(39)(40). In the present study, we have demonstrated a direct binding between MAPKAPK2 and Sophoridine by DARTS assay and CETSA.…”

Section: Discussionsupporting

confidence: 65%

Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2

Wang

Liu

Shao

et al. 2019

Molecular Cancer Research

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Radian Sophorae flavescentis is a traditional Chinese medicine commonly used to treat cancer in China. However, its active components and underlying mechanism remain ambiguous. In this study, we have screened the pharmacokinetic parameters of the main chemical constituents of Radian Sophorae flavescentis by Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform and have found that Sophoridine is one of the best antitumor active ingredients. We have found that MAPKAPK2 is a potential target for Sophoridine by the PharmMapper and KEGG datab-Xase analysis. Moreover, we have found that Sophoridine selectively inactivates phospho-MAPKAPK2 (Thr222) and directly binds into the ATP site of MAPKAPK2 by molecular docking. Furthermore, we have found out a direct binding between MAPKAPK2 and Sophoridine by cellular thermal shift assay and drug affinity responsive targets stability assay.The inhibition effects are further confirmed by Western blot: Sophoridine significantly decreases phospho-MAPKAPK2 (Thr222) in a time-dependent manner, but there is no obvious change in its total expression in colorectal cancer cells. Clinical studies have shown that a higher level of MAPKAPK2 is associated with a poorer percent survival rate (prognosis). Furthermore, a higher level of MAPKAPK2 is positively associated with the enrichment of downregulation of apoptosis and autophagy by gene set enrichment analysis, as well as upregulation of proliferation and cell-cycle arrest. Taken together, our results suggest that the MAPKAPK2 plays a key role in Sophoridineinhibited growth and invasion in colorectal cancers.Implications: These studies show that Sophoridine may be a promising therapeutic strategy that blocks tumorigenesis in colorectal cancers.

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“…In cancer, MK2 signaling was dispensable for the survival of p53 wt non-small-cell lung carcinoma cells [6]; however, we found that MK2 activity was necessary for the survival of p53 wt 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].…”

Section: Discussionmentioning

confidence: 99%

MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

Phoa

Recasens

Gurgis

et al. 2020

Cancers

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MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabilization and senescence. The senescence-inducing efficacy of MK2 inhibition was particularly strong when cells were co-treated with the standard-of-care temozolomide. However, MK2 inhibition also increased the stability of p53 mutants and enhanced the proliferation of p53-mutant stem cells. These observations reveal that in response to DNA damaging chemotherapy, targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype. Thus, MK2 represents a novel drug target in 70% glioblastomas harboring intact TP53 gene. However, targeting MK2 in tumors with TP53 mutations may accelerate disease progression. These findings are highly relevant since TP53 mutations occur in over 50% of all cancers.

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

Cited by 9 publications

References 35 publications

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach

Sophoridine Inhibits Human Colorectal Cancer Progression via Targeting MAPKAPK2

MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

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