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Open AccessArticle

MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

1
School of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, Australia
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Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
3
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia
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Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland
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Tampere Center for Child Health Research, University of Tampere, 33014 Tampere, Finland
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The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
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Department of Pathology, Fimlab Laboratories, Tampere University Hospital, FI-33521 Tampere, Finland
8
Oncogenic Signalling Laboratory, Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA 6009, Australia
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QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia
10
Brain and Mind Research Institute, The University of Sydney, Sydney, New South Wales 2006, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 654; https://doi.org/10.3390/cancers12030654
Received: 10 February 2020 / Revised: 6 March 2020 / Accepted: 6 March 2020 / Published: 11 March 2020
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. View Full-Text
Keywords: glioblastoma; MK2; p53; senescence; temozolomide glioblastoma; MK2; p53; senescence; temozolomide
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MDPI and ACS Style

Phoa, A.F.; Recasens, A.; Gurgis, F.M.S.; Betts, T.A.; Menezes, S.V.; Chau, D.; Nordfors, K.; Haapasalo, J.; Haapasalo, H.; Johns, T.G.; Stringer, B.W.; Day, B.W.; Buckland, M.E.; Lalaoui, N.; Munoz, L. MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells. Cancers 2020, 12, 654. https://doi.org/10.3390/cancers12030654

AMA Style

Phoa AF, Recasens A, Gurgis FMS, Betts TA, Menezes SV, Chau D, Nordfors K, Haapasalo J, Haapasalo H, Johns TG, Stringer BW, Day BW, Buckland ME, Lalaoui N, Munoz L. MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells. Cancers. 2020; 12(3):654. https://doi.org/10.3390/cancers12030654

Chicago/Turabian Style

Phoa, Athena F.; Recasens, Ariadna; Gurgis, Fadi M.S.; Betts, Tara A.; Menezes, Sharleen V.; Chau, Diep; Nordfors, Kristiina; Haapasalo, Joonas; Haapasalo, Hannu; Johns, Terrance G.; Stringer, Brett W.; Day, Bryan W.; Buckland, Michael E.; Lalaoui, Najoua; Munoz, Lenka. 2020. "MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells" Cancers 12, no. 3: 654. https://doi.org/10.3390/cancers12030654

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