4 research outputs found

    Analysis of differential interactome in colorectal adenocarcinoma to identify candidate biomarkers and therapeutics

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    Kolorektal kanser, hem erkeklerde hem de kadınlarda görülen en ölümcül kanser türlerinden biridir. Kolorektal kanserin tedavisi için çeşitli ilaçlar geliştirilmiştir ancak bazı kanser hastalarında ilaç direnci oluşabilir. Örneğin ABCB1 geni tarafından eksprese edilen p-glikoprotein, yüksek ekspresyonu nedeniyle birçok kanser tipinde kemoterapi başarısızlığına neden olmuştur. Bu nedenle hem tedaviye yeni ilaç adayları önermeyi hem de direnç mekanizmasını ters yönde etkilemeyi hedeflemekteyiz. İlk olarak, iki bağımsız veri kümesi için diferansiyel interaktom algoritması gerçekleştirilmiştir. Sonuç olarak, 2214 ve 1625 farklılaştırılmış protein-protein etkileşimleri sırasıyla GEO ve TCGA veri setlerinde bulunmuştur. Ek olarak, her iki veri setinde 25 ortak protein modülü elde edilmiştir. Her modül için temel bileşen analizi ve Kaplan-Meier analizi gerçekleştirilmiştir ve 16 modül önemli tanısal performans sergilerken 6 modül tümör prognozu ile ilişkilendirilmiştir. Ayrıca in vitro canlılık testleri için 4 proteini (CDKN2A, HDAC2, GSK3B, PML) hedefleyen 9 ilaç (abakavir, ribosiklib, eksemestan, vorikonazol, nortriptilin hidroklorür, teofilin, bromokriptin mesilat, budesonid, tolkapon) kullanılmıştır. Abakavir, nortriptilin hidroklorür, eksemestan, tolkapon ve teofilinde önemli inhibisyon profilleri elde edilmiştir. Ayrıca, ABCB1 geninin ko-ekspres ağı, farklı etkileşim numaralarıyla (50, 100, 150 ve 200) oluşturulmuştur. İlaç yeniden konumlandırma simülasyonları sonucunda yedi ilaç (importazole, AG 957, NCGC00182353-01, brazilin, NCGC00181381-01, PD 407824 ve Ro 28-1675) öne çıkarılmıştır. ABCB1 genini hedefleyen aday ilaçların bağlanma afiniteleri, moleküler yerleştirme simülasyonları ile analiz edilmiştir. Bulgularımız, kolorektal kanserde tanı ve tedavi için tamamlayıcı bir strateji sağlayabilir.--------------------Colorectal cancer is one of the most lethal types of cancers common in both men and women. Several drugs are developed for the treatment of colorectal cancer but drug resistance may occur in some cancer patients. For instance, p-glycoprotein which is expressed by the ABCB1 gene may cause chemotherapy failure in several cancer types due to its high expression. Therefore, we aim to propose both novel drug candidates for treatment and to reverse the resistance mechanism. First, the differential interactome algorithm was performed for two independent datasets. Consequently, 2214 and 1625 differentiated protein-protein interactions were found in GEO and TCGA datasets, respectively. Additionally, 25 common protein modules were obtained in both datasets. Principal component analysis and Kaplan-Meier analysis were performed for each module, and 16 modules were exhibited significant diagnostic performance while 6 modules were associated with tumor prognosis. Besides, 9 drugs (abacavir, ribociclib, exemestane, voriconazole, nortriptyline hydrochloride, theophylline, bromocriptine mesylate, budesonide, tolcapone) targeting 4 proteins (CDKN2A, HDAC2, GSK3B, PML) were used to perform in vitro viability assays. Significant inhibition profiles were obtained in abacavir, nortriptyline hydrochloride, exemestane, tolcapone, and theophylline. Moreover, the co-expression network of the ABCB1 gene was constructed with different edge numbers (50, 100, 150, and 200). Seven drugs (importazole, AG 957, NCGC00182353-01, brazilin, NCGC00181381-01, PD 407824, and Ro 28-1675) were featured through the drug repositioning simulations. The binding affinities of the candidate drugs targeting the ABCB1 gene were analyzed by molecular docking simulations. Our findings can provide a complementary strategy for diagnosis and therapy in colorectal cancer

    Pan-cancer mapping of differential protein-protein interactions

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    Abstract Deciphering the variations in the protein interactome is required to reach a systems-level understanding of tumorigenesis. To accomplish this task, we have considered the clinical and transcriptome data on >6000 samples from The Cancer Genome Atlas for 12 different cancers. Utilizing the gene expression levels as a proxy, we have identified the differential protein-protein interactions in each cancer type and presented a differential view of human protein interactome among the cancers. We clearly demonstrate that a certain fraction of proteins differentially interacts in the cancers, but there was no general protein interactome profile that applied to all cancers. The analysis also provided the characterization of differentially interacting proteins (DIPs) representing significant changes in their interaction patterns during tumorigenesis. In addition, DIP-centered protein modules with high diagnostic and prognostic performances were generated, which might potentially be valuable in not only understanding tumorigenesis, but also developing effective diagnosis, prognosis, and treatment strategies

    Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib

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    12 pages, 6 figures, 1 table.-- This is an open access article under the CC BY-NC-ND licenseProteasome inhibitors have great success for their therapeutic potential against hematologic malignancies. First generation proteasome inhibitor bortezomib induced peripheral neuropathy is considered as a limiting factor in chemotherapy and its second-generation counterpart carfilzomib is associated with lower rates of neurotoxicity. The mitochondrial toxicity (mitotoxicity) hypothesis arises from studies with animal models of bortezomib induced peripheral neuropathy. However, molecular mechanisms are not fully elucidated and the role of mitotoxicity in bortezomib and carfilzomib induced neurotoxicity has not been investigated comparatively. Herein, we characterized the neurotoxic effects of bortezomib and carfilzomib at the molecular level in human neuronal cells using LC-MS/MS analysis, flow cytometry, RT-qPCR, confocal microscopy and western blotting. We showed that bortezomib and carfilzomib affected the human neuronal proteome differently, and bortezomib caused higher proteotoxic stress via protein oxidation, protein K48-ubiquitination, heat shock protein expression upregulation and reduction of mitochondria membrane potential. Bortezomib and carfilzomib did not affect the gene expression levels related to mitochondrial dynamics (optic atrophy 1; OPA1, mitofusin 1; MFN1, mitofusin 2; MFN2, fission 1; FIS1, dynamin-related protein 1; DRP1) and overall mitophagy rate whereas, PINK1/Parkin mediated mitophagy gene expressions were altered with both drugs. Bortezomib and carfilzomib caused downregulation of the contents of mitochondrial oxidative phosphorylation complexes, voltage-dependent anion channel 1 (VDAC1) and uncoupling protein 2 (UCP2) similarly. Our findings suggest that, both drugs induce mitotoxicity besides proteotoxic stress in human neuronal cells and the higher incidence of neurotoxicity with bortezomib than carfilzomib is not directly related to mitochondrial pathwaysThis study was supported by The Scientific and Technological Research Council of Turkey - TUBITAK (216S838) and Istanbul University Research Fund (TDK-2017-24221 and TSA-2017-25380). Financial support from the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept for SysMedOS project is gratefully acknowledged. Xunta de Galicia is thankfully acknowledged for the postdoctoral scholarship provided L.MPeer reviewe
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