A PRDX1‐p38α heterodimer amplifies MET‐driven invasion of <i>IDH</i>‐wildtype and <i>IDH</i>‐mutant gliomas

Wirthschaft, Peter; Bode, Julia; Simon, Anika E.M.; Hoffmann, Elisa; Laack, Rebecca van; Krüwel, Thomas; Dietrich, Fabio; Bucher, Delia; Hahn, Artur; Sahm, Felix; Breckwoldt, Michael O.; Kurz, Felix T.; Hielscher, Thomas; Fischer, Bernd; Dross, Nicolas; Almodóvar, Carmen Ruiz de; Deimling, Andreas von; Herold‐Mende, Christel; Plass, Christoph; Boulant, Steeve; Wiestler, Benedikt; Reifenberger, Guido; Lichter, Peter; Wick, Wolfgang; Tews, Björn

doi:10.1002/ijc.31404

Cited by 16 publications

(15 citation statements)

References 47 publications

(70 reference statements)

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“…PRDX1 has been found to up-regulated in multiple cancer tissues. Previous studies have shown that PRDX1 facilitates the infiltrative growth of isocitrate dehydrogenase-wildtype gliomas by forming a heterodimer with p38α 24 . On the contrary, PRDX1 was also confirmed to be a tumor suppresser by protecting PTEN from oxidation-induced inactivation 22 .…”

Section: Discussionmentioning

confidence: 98%

Up-regulation of peroxiredoxin-1 promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer

Lu¹,

Hu²,

Pan³

et al. 2020

J. Cancer

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Objective: To investigate the effect of peroxiredoxin 1 (PRDX1) on the biological behavior of cervical cancer cells and the possible mechanism. Materials and methods: The expression of PRDX1 in human cervical cancer tissues and adjacent non-tumor tissues were detected by immunohistochemistry (IHC). Lentivirus containing PRDX1-cDNA or shRNA against PRDX1 was constructed to overexpress or knockdown PRDX1 in SiHa cervical cancer cells. Cell proliferation was tested by CCK-8 and BrdU incorporation assay and cell apoptosis was evaluated by AnnexinV-PE /7AAD assay. Scratch wound and transwell invasion assay were used to test migration and invasion activity after PRDX1 was overexpressed or suppressed. Furthermore, the effect of PRDX1 on cell proliferation and apoptosis was also studied using a xenograft model of nude mice. Results: The expression of PRDX1 protein was significantly up-regulated in the tumor tissues compared with the paired adjacent non-tumor tissues. Meanwhile, PRDX1 overexpression was associated with tumor stage, lymphatic metastasis and differentiation. Overexpression of PRDX1 significantly promoted proliferation and inhibited apoptosis by increasing the expression of Nanog, proliferating cell nuclear antigen (PCNA), B-cell lymphoma-2 (Bcl-2) and downregulating the expression of Bcl2-associated X protein (BAX) in SiHa cervical cancer cells. Moreover, PRDX1 overexpression increased invasion and migration of SiHa cervical cancer cells via up-regulating the expression of Snail and matrix metalloprotein 9 (MMP-9) and down-regulating the expression of E-cadherin. Knockdown of PRDX1 resulted in the opposite results. The role of PRDX1 in promoting SiHa cervical cancer cell proliferation and inhibiting apoptosis has also been confirmed in vivo in a mouse xenograft model. Conclusions: PRDX1 promoted cell proliferation, migration, and invasion and suppressed apoptosis of cervical cancer possibly via regulating the expression of related protein.

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Section: Discussionmentioning

confidence: 98%

Up-regulation of peroxiredoxin-1 promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer

Lu¹,

Hu²,

Pan³

et al. 2020

J. Cancer

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“…For example, the PRDX1 (Peroxiredoxin 1) this gene encodes a member of the peroxiredoxin family of antioxidant enzymes, which reduce hydrogen peroxide and alkyl hydroperoxides 14 . PRDX1 forms a heterodimer with p38α mitogen-activated protein kinase 14 (MAPK14), stabilizing phosphate-p38α in glioma cells 15 and epigenetic silencing of PRDX1 is frequent in 1p/19q-deleted oligodendroglial tumors and likely contributes to radio-and chemosensitivity of these tumours 16 ; XRCC5 (X-Ray Repair Cross Complementing 5) is the 80-kilodalton subunit of the Ku heterodimer protein, which is also known as ATP-dependant DNA helicase II or DNA repair protein XRCC5. The Polymorphisms of XRCC5 play an important role in astrocytoma prognosis in the Chinese Han population, which could be used in the determination of astrocytoma prognosis in clinical researches 17 ; BCL2L2 (BCL2 Like 2) is a member of the BCL-2 protein family.…”

Section: Discussionmentioning

confidence: 99%

Identification of IFN-β Associated Genes Signature Predicting Overall Survival for Glioblastoma

Cheng¹,

Yuan²,

Li³

et al. 2021

Preprint

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Background: Brain glioblastoma (GBM) is the most common primary malignant tumor of intracranial tumors. The prognosis of this disease is extremely poor. While the introduction of IFN-β regimen in the treatment of gliomas has significantly improved the outcome of patients, the underlying mechanism remains to be elucidated. Materials and methods: mRNA expression profiles and clinicopathological data were downloaded from TCGA-GBM and GSE83300 data set from the GEO. Univariate Cox regression analysis and lasso Cox regression model established a novel four‐gene IFN-β signature (including PRDX1, SEC61B, XRCC5, and BCL2L2) for GBM prognosis prediction. Further, GBM samples (n=50) and normal brain tissues (n=50) were then used for real-time polymerase chain reaction (PCR) experiments. Gene Set Enrichment Analyses (GSEA) was performed to further understand the underlying molecular mechanisms. Pearson correlation was applied to calculate the correlation between the lncRNAs and IFN-β associated genes. A lncRNA with a correlation coefficient |R2| > 0.3 and P < 0.05 was considered to be an IFN-β associated lncRNA.Results: Patients in the high‐risk group shown significantly poorer survival than patients in the low‐risk group. The signature was found to be an independent prognostic factor for GBM survival. Furthermore, GSEA revealed several significantly enriched pathways, which might help explain the underlying mechanisms. Our study identified a novel robust four‐gene IFN-β signature for GBM prognosis prediction. The signature might contain potential biomarkers for metabolic therapy and treatment response prediction in GBM.Conclusions: Our study established a novel IFN-β associated genes signature to predict overall survival of GBM, which may help in clinical decision making for individual treatment.

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“…Indeed, while ABL1 was found to be involved in DNA repair upon irradiation, thus contributing to radioresistance in GBM cells [32], a crucial role in linking RNA processing with signal transduction of ERK2 has recently been unveiled [33]. Moreover, activation of the MAPK14 signaling pathway has been previously shown to correlate with poor prognosis in GBM patients, increased tumor invasiveness and aggressive phenotype [34][35][36][37][38]. Here, in vitro kinase assays confirmed that MBZ could directly inhibit the kinase activity of these proteins, thus confirming their status of direct molecular targets of MBZ.…”

Section: Discussionmentioning

confidence: 99%

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

Ariey-Bonnet

Carrasco

Grand

et al. 2020

Preprint

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The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro. Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly up-regulated at the gene level in glioblastoma as compared to normal brain tissue. Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2 and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose-dependent manner, with a high potency against MAPK14. Its direct binding to MAPK14 was further validated in vitro and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases. Significance StatementThis study provides a framework to investigate drug polypharmacology by rapidly identifying novel molecular targets of already-approved drugs. It unveils a new mechanism involved in the anticancer activity of anti-helminthic drug, mebendazole, which is currently being repurposed for the treatment of brain tumors. By helping to decipher the mechanism(s) of action of repurposed drugs in their new indications, this approach could contribute to the development of safer and more effective therapeutic strategies in oncology and beyond.

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A PRDX1‐p38α heterodimer amplifies MET‐driven invasion of IDH‐wildtype and IDH‐mutant gliomas

Cited by 16 publications

References 47 publications

Up-regulation of peroxiredoxin-1 promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer

Up-regulation of peroxiredoxin-1 promotes cell proliferation and metastasis and inhibits apoptosis in cervical cancer

Identification of IFN-β Associated Genes Signature Predicting Overall Survival for Glioblastoma

In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

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