MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells
Open Access
- 11 March 2020
- Vol. 12 (3), 654
- https://doi.org/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.Funding Information
- National Health and Medical Research Council (APP1163484)
This publication has 53 references indexed in Scilit:
- Damage-induced DNA replication stalling relies on MAPK-activated protein kinase 2 activityProceedings of the National Academy of Sciences of the United States of America, 2013
- p53 Dynamics Control Cell FateScience, 2012
- DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA StabilizationMolecular Cell, 2010
- p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replicationProceedings of the National Academy of Sciences of the United States of America, 2010
- The Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in the p38/TNF-α Pathway of Systemic and Cutaneous InflammationJournal of Investigative Dermatology, 2010
- The Neuropharmacokinetics of Temozolomide in Patients with Resectable Brain Tumors: Potential Implications for the Current Approach to ChemoradiationClinical Cancer Research, 2009
- MK2 regulates the early stages of skin tumor promotionCarcinogenesis: Integrative Cancer Research, 2009
- Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trialThe Lancet Oncology, 2009
- p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK/MK2 Pathway for Survival after DNA DamageCancer Cell, 2007
- HDM2 phosphorylation by MAPKAP kinase 2Oncogene, 2005