期刊
FASEB BIOADVANCES
卷 2, 期 2, 页码 126-144出版社
WILEY
DOI: 10.1096/fba.2019-00071
关键词
ccRCC; cell signaling; R1TNF; R2TNF; STAT3
资金
- NIHR Cambridge Biomedical Research Centre
- Addenbrooke's Charitable Trust
Clear 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 serine(727) but not tyrosine(705), resulting in pSTAT3Ser(727) 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.
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