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dc.contributor.authorBradley, John R
dc.contributor.authorWang, Jun
dc.contributor.authorPacey, Simon
dc.contributor.authorWarren, Anne Y
dc.contributor.authorPober, Jordan S
dc.contributor.authorAl-Lamki, Rafia S
dc.date.accessioned2020-04-04T00:46:24Z
dc.date.available2020-04-04T00:46:24Z
dc.date.issued2020-01-03
dc.identifier.issn2573-9832
dc.identifier.otherPMC7003657
dc.identifier.other32123862
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/304087
dc.description.abstractClear cell renal cell carcinoma (ccRCC) contains cancer stem-like cells (CSCs) that express CD133 (ccRCC-CD133+). CSCs are rarely in cell cycle and, as nonproliferating cells, resist most chemotherapeutic agents. Previously, we reported that tumor necrosis factor receptor-2 (TNFR2) signaling promotes the cell cycle entry of ccRCC-CD133+CSCs, rendering them susceptible to cell-cycle-dependent chemotherapeutics. Here, we describe a TNFR2-activated signaling pathway in ccRCC-CD133+CSCs that is required for cell survival. Wild-type (wt)TNF or R2TNF but not R1TNF (TNF muteins that selectively bind to TNFR2 and TNFR1) induces phosphorylation of signal transducer and activator of transcription 3 (STAT3) on serine727 but not tyrosine705, resulting in pSTAT3Ser727 translocation to and colocalization with TNFR2 in mitochondria. R2TNF signaling activates a kinase cascade involving the phosphorylation of VEGFR2, PI-3K, Akt, and mTORC. Inhibition of any of the kinases or siRNA knockdown of TNFR2 or STAT3 promotes cell death associated with mitochondrial morphological changes, cytochrome c release, generation of reactive oxygen species, and TUNEL+cells expressing phosphorylated mixed lineage kinase-like (MLKL). Pretreatment with necrostatin-1 is more protective than z-VAD.fmk, suggesting that most death is necroptotic and TNFR2 signaling promotes cell survival by preventing mitochondrial-mediated necroptosis. These data suggest that a TNFR2 selective agonist may offer a potential therapeutic strategy for ccRCC.
dc.languageeng
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2573-9832
dc.sourcenlmid: 101733210
dc.subjectStat3
dc.subjectCell signaling
dc.subjectCcrcc
dc.subjectR1tnf
dc.subjectR2tnf
dc.titleTumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.
dc.typeArticle
dc.date.updated2020-04-04T00:46:23Z
prism.endingPage144
prism.issueIdentifier2
prism.publicationNameFASEB bioAdvances
prism.startingPage126
prism.volume2
dc.identifier.doi10.17863/CAM.51169
rioxxterms.versionofrecord10.1096/fba.2019-00071
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
pubs.funder-project-idKidney Research UK (SP/GW1/2012)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International