MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells
MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While <i>TP53</i> deletion is rare in glioblastomas, these tumors often carry <i>TP53</i> mutations. Here, we show that MK...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/654 |
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| author | Athena F. Phoa Ariadna Recasens Fadi M. S. Gurgis Tara A. Betts Sharleen V. Menezes Diep Chau Kristiina Nordfors Joonas Haapasalo Hannu Haapasalo Terrance G. Johns Brett W. Stringer Bryan W. Day Michael E. Buckland Najoua Lalaoui Lenka Munoz |
| author_facet | Athena F. Phoa Ariadna Recasens Fadi M. S. Gurgis Tara A. Betts Sharleen V. Menezes Diep Chau Kristiina Nordfors Joonas Haapasalo Hannu Haapasalo Terrance G. Johns Brett W. Stringer Bryan W. Day Michael E. Buckland Najoua Lalaoui Lenka Munoz |
| author_sort | Athena F. Phoa |
| collection | DOAJ |
| description | MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While <i>TP53</i> deletion is rare in glioblastomas, these tumors often carry <i>TP53</i> mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53<sup>wt</sup> 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 <i>TP53</i> gene. However, targeting MK2 in tumors with <i>TP53</i> mutations may accelerate disease progression. These findings are highly relevant since <i>TP53</i> mutations occur in over 50% of all cancers. |
| first_indexed | 2024-03-12T08:29:42Z |
| format | Article |
| id | doaj.art-559318a9d3d9438886f8d65eede0b009 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:29:42Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-559318a9d3d9438886f8d65eede0b0092023-09-02T17:49:04ZengMDPI AGCancers2072-66942020-03-0112365410.3390/cancers12030654cancers12030654MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma CellsAthena F. Phoa0Ariadna Recasens1Fadi M. S. Gurgis2Tara A. Betts3Sharleen V. Menezes4Diep Chau5Kristiina Nordfors6Joonas Haapasalo7Hannu Haapasalo8Terrance G. Johns9Brett W. Stringer10Bryan W. Day11Michael E. Buckland12Najoua Lalaoui13Lenka Munoz14School of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, AustraliaDepartment of Pediatrics, Tampere University Hospital, 33521 Tampere, FinlandThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaDepartment of Pathology, Fimlab Laboratories, Tampere University Hospital, FI-33521 Tampere, FinlandOncogenic Signalling Laboratory, Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA 6009, AustraliaQIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, AustraliaQIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, AustraliaSchool of Medical Sciences, Charles Perkins Centre and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales 2006, AustraliaMAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While <i>TP53</i> deletion is rare in glioblastomas, these tumors often carry <i>TP53</i> mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53<sup>wt</sup> 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 <i>TP53</i> gene. However, targeting MK2 in tumors with <i>TP53</i> mutations may accelerate disease progression. These findings are highly relevant since <i>TP53</i> mutations occur in over 50% of all cancers.https://www.mdpi.com/2072-6694/12/3/654glioblastomamk2p53senescencetemozolomide |
| spellingShingle | Athena F. Phoa Ariadna Recasens Fadi M. S. Gurgis Tara A. Betts Sharleen V. Menezes Diep Chau Kristiina Nordfors Joonas Haapasalo Hannu Haapasalo Terrance G. Johns Brett W. Stringer Bryan W. Day Michael E. Buckland Najoua Lalaoui Lenka Munoz MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells Cancers glioblastoma mk2 p53 senescence temozolomide |
| title | MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells |
| title_full | MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells |
| title_fullStr | MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells |
| title_full_unstemmed | MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells |
| title_short | MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells |
| title_sort | mk2 inhibition induces p53 dependent senescence in glioblastoma cells |
| topic | glioblastoma mk2 p53 senescence temozolomide |
| url | https://www.mdpi.com/2072-6694/12/3/654 |
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