A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling

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dc.contributor.authorClem, Brian F.
dc.contributor.authorClem, Amy L.
dc.contributor.authorGoswami, Umesh
dc.contributor.authorArumugam, Sengodagounder
dc.contributor.authorTelang, Sucheta
dc.contributor.authorTrent, John O.
dc.contributor.authorChesney, Jason A.
dc.contributor.buuauthorYalçın, Abdullah
dc.contributor.departmentUludağ Üniversitesi/Veterinerlik Fakültesi/Biyokimya Anabilim Dalı.tr_TR
dc.contributor.orcid0000-0001-8519-8375tr_TR
dc.contributor.researcheridABI-4164-2020tr_TR
dc.contributor.researcheridA-5261-2016tr_TR
dc.contributor.scopusid36857831000tr_TR
dc.date.accessioned2021-11-22T10:37:13Z
dc.date.available2021-11-22T10:37:13Z
dc.date.issued2011-07
dc.description.abstractCholine kinase-alpha expression and activity are increased in multiple human neoplasms as a result of growth factor stimulation and activation of cancer-related signaling pathways. The product of choline kinase-alpha, phosphocholine, serves as an essential metabolic reservoir for the production of phosphatidylcholine, the major phospholipid constituent of membranes and substrate for the production of lipid second messengers. Using in silico screening for small molecules that may interact with the choline kinase-alpha substrate binding domain, we identified a novel competitive inhibitor, N-(3,5-dimethylphenyl)-2-[[5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl] sulfanyl] acetamide (termed CK37) that inhibited purified recombinant human choline kinase-alpha activity, reduced the steady-state concentration of phosphocholine in transformed cells, and selectively suppressed the growth of neoplastic cells relative to normal epithelial cells. Choline kinase-alpha activity is required for the downstream production of phosphatidic acid, a promoter of several Ras signaling pathways. CK37 suppressed mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT signaling, disrupted actin cytoskeletal organization, and reduced plasma membrane ruffling. Finally, administration of CK37 significantly decreased tumor growth in a lung tumor xenograft mouse model, suppressed tumor phosphocholine, and diminished activating phosphorylations of extracellular signal-regulated kinase and AKT in vivo. Together, these results further validate choline kinase-alpha as a molecular target for the development of agents that interrupt Ras signaling pathways, and indicate that receptor-based computational screening should facilitate the identification of new classes of choline kinase-alpha inhibitors.en_US
dc.description.sponsorshipBrown Foundationen_US
dc.description.sponsorshipNCCRR (1P20 RR18733)en_US
dc.description.sponsorshipJames Graham Brown Cancer Centeren_US
dc.description.sponsorshipKy Lung Cancer Research Programen_US
dc.description.sponsorshipUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) (2R56CA116428-0509), (R01CA116428), (R56CA116428)en_US
dc.description.sponsorshipUnited States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Research Resources (NCRR) (P20RR018733)en_US
dc.description.sponsorshipKansas Technology Enterprise Corporationen_US
dc.description.sponsorshipNational Science Foundation’s EPSCoR Program (EPS-0236913)en_US
dc.description.sponsorshipState of Kansasen_US
dc.identifier.citationClem, BF. vd. (2011). " A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling ". Oncogene, 30(30), 3370-3380.en_US
dc.identifier.endpage3380tr_TR
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.issue30tr_TR
dc.identifier.pubmed21423211tr_TR
dc.identifier.scopus2-s2.0-79960835666tr_TR
dc.identifier.startpage3370tr_TR
dc.identifier.urihttps://doi.org/10.1038/onc.2011.51
dc.identifier.urihttps://www.nature.com/articles/onc201151
dc.identifier.urihttp://hdl.handle.net/11452/22749
dc.identifier.volume30tr_TR
dc.identifier.wos000293215700007tr_TR
dc.indexed.pubmedPubmeden_US
dc.indexed.scopusScopusen_US
dc.indexed.wosSCIEen_US
dc.language.isoenen_US
dc.publisherSpringernatureen_US
dc.relation.collaborationYurt dışıtr_TR
dc.relation.journalOncogeneen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergitr_TR
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectBiochemistry & molecular biologyen_US
dc.subjectOncologyen_US
dc.subjectCell biologyen_US
dc.subjectGenetics & heredityen_US
dc.subjectChemotherapyen_US
dc.subjectCholine kinaseen_US
dc.subjectMetabolismen_US
dc.subjectIn silicoen_US
dc.subjectPhosphocholineen_US
dc.subjectBreast-cancer-cellsen_US
dc.subjectPhosphatidic-aciden_US
dc.subjectPhospholipase-Den_US
dc.subjectProstate-canceren_US
dc.subjectRas activationen_US
dc.subjectGrowth-factorsen_US
dc.subjectPhosphatidylcholineen_US
dc.subjectInhibitorsen_US
dc.subjectRaf-1en_US
dc.subjectP-31en_US
dc.subject.emtreeCholine kinaseen_US
dc.subject.emtreeEnzyme inhibitoren_US
dc.subject.emtreeMitogen activated protein kinaseen_US
dc.subject.emtreen (3,5 dimethylphenyl) 2 [[5 (4 ethylphenyl) 1h 1,2,4 triazol 3 yl]sulfanyl] acetamideen_US
dc.subject.emtreePhosphatidic aciden_US
dc.subject.emtreePhosphatidylcholineen_US
dc.subject.emtreePhosphatidylinositol 3 kinaseen_US
dc.subject.emtreePhosphorylcholineen_US
dc.subject.emtreeProtein kinase Ben_US
dc.subject.emtreeUnclassified drugen_US
dc.subject.emtreeAnimal experimenten_US
dc.subject.emtreeAnimal modelen_US
dc.subject.emtreeArticleen_US
dc.subject.emtreeCancer inhibitionen_US
dc.subject.emtreeComputer modelen_US
dc.subject.emtreeControlled studyen_US
dc.subject.emtreeEnzyme activityen_US
dc.subject.emtreeHumanen_US
dc.subject.emtreeHuman cellen_US
dc.subject.emtreeLung tumoren_US
dc.subject.emtreeMolecular interactionen_US
dc.subject.emtreeMouseen_US
dc.subject.emtreeNonhumanen_US
dc.subject.emtreePriority journalen_US
dc.subject.emtreeProtein expressionen_US
dc.subject.emtreeProtein targetingen_US
dc.subject.emtreeSecond messengeren_US
dc.subject.emtreeSignal transductionen_US
dc.subject.emtreeSteady stateen_US
dc.subject.emtreeTumor xenograften_US
dc.subject.meshAcetamidesen_US
dc.subject.meshActinsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCell membraneen_US
dc.subject.meshCell proliferationen_US
dc.subject.meshCholine kinaseen_US
dc.subject.meshComputational biologyen_US
dc.subject.meshEnzyme inhibitorsen_US
dc.subject.meshExtracellular signal-regulated MAP kinasesen_US
dc.subject.meshFemaleen_US
dc.subject.meshHela cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshMAP kinase signaling systemen_US
dc.subject.meshMiceen_US
dc.subject.meshMitogen-activated protein kinasesen_US
dc.subject.meshModels, molecularen_US
dc.subject.meshPhosphatidylinositol 3-kinasesen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshPhosphorylcholineen_US
dc.subject.meshProtein conformationen_US
dc.subject.meshProto-oncogene proteins c-akten_US
dc.subject.meshProto-oncogene proteins p21(ras)en_US
dc.subject.meshTriazolesen_US
dc.subject.meshXenograft model antitumor assaysen_US
dc.subject.scopusCholine Kinase; Phosphoethanolamine; N Acetylaspartic Aciden_US
dc.subject.wosBiochemistry & molecular biologyen_US
dc.subject.wosOncologyen_US
dc.subject.wosCell biologyen_US
dc.subject.wosGenetics & heredityen_US
dc.titleA novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signalingen_US
dc.typeArticle
dc.wos.quartileQ1en_US

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