MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells.

Athena F Phoa,Fadi M S Gurgis,Ariadna Recasens,Joonas Haapasalo,Michael E Buckland,Tara A Betts,Diep Chau,Terrance G Johns,Brett W Stringer,Najoua Lalaoui,Sharleen V Menezes,Kristiina Nordfors,Lenka Munoz,Hannu Haapasalo,Bryan W Day

doi:10.3390/cancers12030654

Abstract

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.

Highlights

MAPK-activated protein kinase 2 (MAPKAPK2 or MK2) is activated via p38 MAPK-mediated phosphorylation in response to stress and exhibits diverse roles in inflammation and cancer [1].Cancers 2020, 12, 654; doi:10.3390/cancers12030654 www.mdpi.com/journal/cancersPro-tumorigenic MK2 functions include the deregulation of apoptosis in skin tumors [2], enhanced metastasis of breast tumors [3] and polarization of macrophages into their M2 state that promotes angiogenesis in colorectal cancer [4]
To investigate the relevance of MK2 in gliomas, we examined the Cancer Genome Atlas (TCGA)
Since MK2 activates p53-degrading HDM2 ligase through the phosphorylation of Ser166 [35], we examined the effect of MK2 inhibition on the HDM2-p53 pathway

Summary

Introduction

MAPK-activated protein kinase 2 (MAPKAPK2 or MK2) is activated via p38 MAPK-mediated phosphorylation in response to stress and exhibits diverse roles in inflammation and cancer [1].Cancers 2020, 12, 654; doi:10.3390/cancers12030654 www.mdpi.com/journal/cancersPro-tumorigenic MK2 functions include the deregulation of apoptosis in skin tumors [2], enhanced metastasis of breast tumors [3] and polarization of macrophages into their M2 state that promotes angiogenesis in colorectal cancer [4]. MK2 has been successfully targeted to improve the efficacy of radiation therapy [5] and various cancer drugs, such as cisplatin [6], doxorubicin [7], Chk kinase inhibitors [8] and Smac mimetics [9]. A number of different mechanisms by which MK2 promotes tumor growth and therapy resistance have been reported, there are limited data on MK2 signaling in gliomas [10,11,12,13,14]. Patients with lower-grade gliomas have better survival prognosis than glioblastoma patients, lower-grade glioma is a uniformly fatal disease in young adults, as all tumors eventually progress to secondary glioblastomas and cause death within 7 years [16].

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Conclusion