IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

Khurshed, Mohammed; Aarnoudse, Niels; Hulsbos, Renske; Hira, Vashendriya V.V.; Laarhoven, Hanneke W. M. van; Wilmink, Johanna W.; Molenaar, Remco J.; Noorden, C. J. F. Van

doi:10.1096/fj.201800547r

Cited by 29 publications

(26 citation statements)

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“…However, the tumor-suppressor functions of these proteins in gliomas, including the vascular normalization that we have described here, could represent a severe pitfall for these approaches. In fact, the treatment with IDHmut inhibitors has been associated with a radioprotective effect (41) and a decreased sensitivity to cisplatin (42). Regarding IDHwt gliomas, our results suggest that microtubule stabilizers could imitate Tau function and reduce the aggressiveness of the tumors, which could render them sensitive to conventional chemotherapy (Fig.…”

Section: Tau Expression Is a Surrogate Marker Of The Less Aggressive mentioning

confidence: 71%

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Gargini

Segura-Collar

Herránz

et al. 2019

Preprint

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One Sentence SummaryTau, which is induced by IDH mutations, inhibits the EGFR/NF-kB/TAZ axis and impairs the mesenchymal/pericyte-like transformation of glioma cells, normalizing the vasculature and impairing tumor aggressiveness. AbstractMutant IDH1/2 gliomas represent a more indolent form of cancer. However, how this group of tumors evolve, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau, a gene classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wild-type and mutant IDH1/2 in gliomas. Moreover, the level of Tau decreases when the tumor progresses. Besides, Tau is almost absent from tumors with EGFR mutations, whereas its expression is inversely correlated with overall survival in gliomas carrying wild-type or amplified EGFR. Here, we demonstrate that the overexpression of Tau, through the stabilization of microtubules, impairs the mesenchymal/pericyte-like transformation of glioma cells by blocking the EGFR-NFB-TAZ axis. However, mutant EGFR induces a constitutive activation of this pathway, which is no longer sensitive to Tau. By inhibiting the phenotypic plasticity of EGFRamp/wt glioma cells, Tau protein inhibits angiogenesis and favors vascular normalization, decreasing tumor aggressiveness and rendering the tumors more sensitive to chemotherapy.

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Section: Tau Expression Is a Surrogate Marker Of The Less Aggressive mentioning

confidence: 71%

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Gargini

Segura-Collar

Herránz

et al. 2019

Preprint

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“…Similarly, many other mitochondria-resident APE1-PPIs were found to be commonly up-regulated in the analyzed datasets. Among these, it is worth mentioning: (i) SHMT2 (serine hydroxymethyltransferase), that mainly localizes to the matrix, nucleoid and inner membranes, and is known to be targeted by c-myc for cell survival, with various studies confirming its bad prognostic power in different cancer types [87][88][89][90][91] ; (ii) pro-apoptotic protein SLC25A6 (mitochondrial ADP/ATP carrier-3, AAC3) 92,93 ; (iii) ROS regulating respiratory complex III protein UQCRC2 (ubiquinol-cytochrome c reductase complex core protein 2) 94 ; (iv) respiratory complex II protein SDHB (succinate dehydrogenase B) 95 ; v) fatty acid βoxidation proteins ETFA (electron transfer flavoprotein subunit alpha) 96,97 and ACAA2 (acetyl-CoA acyltransferase 2) 98 ; vi) bad prognostic multifunctional LGALS3 (galectin-3) protein 99 ; (vii) autoimmunity protein HARS (histidyl-tRNA synthetase) 100 ; (viii) oxidative damage control protein IDH1 (isocitrate dehydrogenase 1) 101 . Additional matrix proteins were found being up-regulated in LIHC and LUAD, while down-regulated in PAAD; they included fatty acid β-oxidation proteins ECHS1 (enoyl coenzyme A hydratase short chain 1) 102 and ETFB (electron transfer flavoprotein subunit beta) 103 , multifunctional protein 17β-HSD10 (17β-hydroxysteroid dehydrogenase type 10, encoded by HSD17B10) 104 and mitochondrial protein processor PMPCA (mitochondrial-processing peptidase subunit alpha) 105 .…”

Section: Discussionmentioning

confidence: 99%

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Ayyildiz

Antoniali

D’Ambrosio

et al. 2020

Sci Rep

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APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA-and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368.Alteration of DNA repair mechanisms is an important hallmark of cancer cells, and plays a role both in the onset of an initial cancerous phenotype and in tumor progression. Tumor cells can develop drug resistance through repair mechanisms that counteract the DNA damage induced by chemotherapy or radiotherapy 1,2 . Thus, specific DNA repair inhibitors are often combined with DNA-damaging agents to improve therapy efficacy. Emerging evidences in tumor biology suggest that: i) protein-protein interactions (PPIs) specifically modulate both canonical and non-canonical roles of DNA repair enzymes; ii) RNA processing pathways participate in DNA-Damage Response (DDR); iii) defects in the above-mentioned regulatory mechanisms are associated with cancer genomic instability 3 . Very recent studies clearly show that many DNA repair proteins are associated with those involved in RNA metabolism, proving a role of their interactome network in undertaking non-canonical functions affecting gene expression in tumors. In addition, novel studies have shown that interaction of DDR components and miRNA biogenesis process is linked to cancer development 2 . In the context of these emerging lines, we already demonstrated the crucial role that enzymes belonging to the base excision DNA repair (BER) pathway play 4 . In particular, we showe...

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“…However, in comparison to wild‐type IDH1, mutant IDH1 expressing cells are endowed with higher sensitivity to radiation and chemotherapy as they exhibit higher levels of reactive oxygen species, and breaks in DNA causing cell death. In contrast, treatments with mIDH1i circumvent the sensitivity of mutant IDH1 cells to therapy leading to resistance . Therefore, we suggest that FOXM1 maybe a better therapeutic target to abrogate mutant IDH1 expression in gliomas; as diverse chemical moieties inhibit FOXM1 in preclinical models leading to favourable outcomes .…”

Section: Discussionmentioning

confidence: 92%

Abundance of d‐2‐hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1‐expressing cells

et al. 2019

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Isocitrate dehydrogenases (IDHs) are metabolic enzymes that are mutated in several cancers, resulting in overproduction of d‐2‐hydroxyglutarate (D‐2HG). However, the signalling pathways and factors that regulate mutant IDHs or their metabolites remain elusive. Here, we report that in synchronized cells and cells treated with anti‐mitotic agents, wild‐type and mutant IDH proteins are induced maximally in G2/M. Moreover, mutant IDH1‐expressing cells arrested in G2/M harbour high D2HG levels. Genetic or pharmacological perturbation of Forkhead box protein M1 (FOXM1) abrogates the levels of IDH1 mRNA, protein and D2HG in G2/M. Conversely, overexpression of FOXM1 or hyperactive FOXM1 activates the IDH1 promoter and increases the abundance of its protein levels. In summary, our results show that in G2/M, higher D2HG levels are dependent on FOXM1‐mediated transcription of IDH1.

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IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

Cited by 29 publications

References 50 publications

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

Abundance of d‐2‐hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1‐expressing cells

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