MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

Phoa, Athena; Recasens, Ariadna; Gurgis, Fadi; 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

doi:10.3390/cancers12030654

Cited by 6 publications

(3 citation statements)

References 53 publications

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“…Glioma patients with the highest MK2 activity had the worst survival rate, and MK2 inhibition strongly attenuated glioblastoma cell proliferation through the stabilization of p53 and induction of senescence (79). Interestingly, synthetic lethality between MK2 and p53 deletion was demonstrated in a non-small-cell lung cancer mouse model, showing that in response to genotoxic chemotherapy, MK2 is essential for the survival of tumor cells that lack functional p53 but is dispensable in p53-proficient cells (80).…”

Section: Genotoxic Stress and The Dna-damage Responsementioning

confidence: 99%

MAPK-Activated Protein Kinases: Servant or Partner?

Ronkina

Gaestel

2022

Annu. Rev. Biochem.

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Mitogen-activated protein kinase (MAPK)-activated protein kinases (MAPKAPKs) are defined by their exclusive activation by MAPKs. They can be activated by classical and atypical MAPKs that have been stimulated by mitogens and various stresses. Genetic deletions of MAPKAPKs and availability of highly specific small-molecule inhibitors have continuously increased our functional understanding of these kinases. MAPKAPKs cooperate in the regulation of gene expression at the level of transcription; RNA processing, export, and stability; and protein synthesis. The diversity of stimuli for MAPK activation, the cross talk between the different MAPKs and MAPKAPKs, and the specific substrate pattern of MAPKAPKs orchestrate immediate-early and inflammatory responses in space and time and ensure proper control of cell growth, differentiation, and cell behavior. Hence, MAPKAPKs are promising targets for cancer therapy and treatments for conditions of acute and chronic inflammation, such as cytokine storms and rheumatoid arthritis. Expected final online publication date for the Annual Review of Biochemistry, Volume 91 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Genotoxic Stress and The Dna-damage Responsementioning

confidence: 99%

MAPK-Activated Protein Kinases: Servant or Partner?

Ronkina

Gaestel

2022

Annu. Rev. Biochem.

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“…Alongside WWOX / POLE4 / HSF2BP , twelve genes from the network exhibited the expression profile that is consistent between patients and cell lines. These genes were DUSP4 ( Prabhakar et al, 2014 ), SLC36A1 ( Schaffenrath et al, 2021 ; Wei et al, 2022 ), EPB41L1 ( Han et al, 2019 ), PNMA2 ( Alhajala et al, 2018 ), YPEL3 ( Phoa et al, 2020 ), SEC11C ( Pernia et al, 2020 ), FGGY ( Salzillo et al, 2016 ; Smith et al, 2021 ), LSM2 ( Sun et al, 2022 ), IGFBP7 ( Jiang et al, 2008 ), STOML2 ( Qu et al, 2019 ; Ma et al, 2021 ), PKM ( Mukherjee et al, 2013 ; El Atat et al, 2023 ), and SYNPO ( Ning et al, 2021 ; Krishna et al, 2023 ). Some of them were shortly described in previous sections, but the possible roles of all genes are recapitulated in Figure 5A , where the results of PCA are also presented.…”

Section: Resultsmentioning

confidence: 99%

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Kałuzińska-Kołat,

Kołat,

Kośla

et al. 2023

Front. Neurosci.

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IntroductionGlioblastoma (GBM) is notorious for its clinical and molecular heterogeneity, contributing to therapeutic failure and a grim prognosis. WWOX is one of the tumor suppressor genes important in nervous tissue or related pathologies, which was scarcely investigated in GBM for reliable associations with prognosis or disease progression despite known alterations. Recently, we observed a phenotypic heterogeneity between GBM cell lines (U87MG, T98G, U251MG, DBTRG-05MG), among which the anti-GBM activity of WWOX was generally corresponding, but colony growth and formation were inconsistent in DBTRG-05MG. This prompted us to investigate the molecular landscapes of these cell lines, intending to translate them into the clinical context.MethodsU87MG/T98G/U251MG/DBTRG-05MG were subjected to high-throughput sequencing, and obtained data were explored via weighted gene co-expression network analysis, differential expression analysis, functional annotation, and network building. Following the identification of the most relevant DBTRG-distinguishing driver genes, data from GBM patients were employed for, e.g., differential expression analysis, survival analysis, and principal component analysis.ResultsAlthough most driver genes were unique for each cell line, some were inversely regulated in DBTRG-05MG. Alongside driver genes, the differentially-expressed genes were used to build a WWOX-related network depicting protein–protein interactions in U87MG/T98G/U251MG/DBTRG-05MG. This network revealed processes distinctly regulated in DBTRG-05MG, e.g., microglia proliferation or neurofibrillary tangle assembly. POLE4 and HSF2BP were selected as DBTRG-discriminating driver genes based on the gene significance, module membership, and fold-change. Alongside WWOX, POLE4 and HSF2BP expression was used to stratify patients into cell lines-resembling groups that differed in, e.g., prognosis and treatment response. Some differences from a WWOX-related network were certified in patients, revealing genes that clarify clinical outcomes. Presumably, WWOX overexpression in DBTRG-05MG resulted in expression profile change resembling that of patients with inferior prognosis and drug response. Among these patients, WWOX may be inaccessible for its partners and does not manifest its anti-cancer activity, which was proposed in the literature but not regarding glioblastoma or concerning POLE4 and HSF2BP.ConclusionCell lines data enabled the identification of patients among which, despite high expression of WWOX tumor suppressor, no advantageous outcomes were noted due to the cancer-promoting profile ensured by other genes.

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“…The cell cycle arrest prevents the original tumorigenesis. Moreover, under the stress of radiotherapy [ 34 ] or chemotherapy [ 35 ] without a fatal dose, cells suffer DNA damage and are driven into the premature senescence instead of apoptosis to seek survival. Moreover, under stressful microenvironment, epigenomic perturbations also regulate senescence process.…”

Section: Cell Senescencementioning

confidence: 99%

Cell Senescence: A Nonnegligible Cell State under Survival Stress in Pathology of Intervertebral Disc Degeneration

Zhang

Yang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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The intervertebral disc degeneration (IDD) with increasing aging mainly manifests as low back pain (LBP) accompanied with a loss of physical ability. These pathological processes can be preliminarily interpreted as a series of changes at cellular level. In addition to cell death, disc cells enter into the stagnation with dysfunction and deteriorate tissue microenvironment in degenerative discs, which is recognized as cell senescence. During aging, many intrinsic and extrinsic factors have been proved to have strong connections with these cellular senescence phenomena. Growing evidences of these connections require us to gather up critical cues from potential risk factors to pathogenesis and relative interventions for retarding cell senescence and attenuating degenerative changes. In this paper, we try to clarify another important cell state apart from cell death in IDD and discuss senescence-associated changes in cells and extracellular microenvironment. Then, we emphasize the role of oxidative stress and epigenomic perturbations in linking risk factors to cell senescence in the onset of IDD. Further, we summarize the current interventions targeting senescent cells that may exert the benefits of antidegeneration in IDD.

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MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells

Cited by 6 publications

References 53 publications

MAPK-Activated Protein Kinases: Servant or Partner?

MAPK-Activated Protein Kinases: Servant or Partner?

Molecular landscapes of glioblastoma cell lines revealed a group of patients that do not benefit from WWOX tumor suppressor expression

Cell Senescence: A Nonnegligible Cell State under Survival Stress in Pathology of Intervertebral Disc Degeneration

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