Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.
Bradley, John R
Warren, Anne Y
Pober, Jordan S
Al-Lamki, Rafia S
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Bradley, J. R., Wang, J., Pacey, S., Warren, A. Y., Pober, J. S., & Al-Lamki, R. S. (2020). Tumor necrosis factor receptor-2 signaling pathways promote survival of cancer stem-like CD133+ cells in clear cell renal carcinoma.. FASEB bioAdvances, 2 (2), 126-144. https://doi.org/10.1096/fba.2019-00071
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 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.
Stat3, Cell signaling, Ccrcc, R1tnf, R2tnf
Kidney Research UK (SP/GW1/2012)
External DOI: https://doi.org/10.1096/fba.2019-00071
This record's URL: https://www.repository.cam.ac.uk/handle/1810/304087
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/