Tumor necrosis factor receptor‐2 signaling pathways promote survival of cancer stem‐like CD133 ⁺ cells in clear cell renal carcinoma

Abstract

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.

Bioinformatics Analyses of the Transcriptome Reveal Ube3a-Dependent Effects on Mitochondrial-Related Pathways

“…One way to induce mitochondrial-related signaling pathways is to stimulate cells with the cytokine tumor necrosis factor-α (TNFα). TNFα stimulation has been shown to elicit a wide range of cellular responses in almost all cell types, including cell death, survival, differentiation, and proliferation [37][38][39], and many of these activated pathways involve or affect the mitochondria. For example, TNFα stimulation induced translocation of mitochondria from a dispersed distribution to a perinuclear cluster [39].…”

Tumor Necrosis Factor α: Taking a Personalized Road in Cancer Therapy

“…In parallel, mouse studies have connected reduced TNBC growth after chemotherapy with elevated presence of CD8+ TNFR2+ TILs, presumably cytotoxic T cells (CTLs) ( 68 , 69 ), agreeing with TNFR2 being required for cytotoxic activities of CD8+ T cells ( 66 ). Moreover, unlike several publications connecting TNFR2 expression by cancer cells to pro-tumor phenotypes ( 63 , 70 – 72 ), TNFR2 was found to be protective in breast cancer, as demonstrated by using a mouse model with the loss of one of the TNFR2 alleles ( 73 ).…”

Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers

“…Conversely, permeability problems and, at the same time, the indiscriminate toxicity of AAC inhibitors [ 4 , 23 ], able to target simultaneously AACs from several tissues, might be avoided by chemical conjugation of the CXT (and future CXT structurally related ligands) to a specific monoclonal antibody (mAb) directed against plasma membrane receptors expressed selectively on cancer cells [ 86 , 87 , 88 ]. The mAbs should grant the specific delivery of the investigated inhibitors to cancer cells expressing specific (or highly selective) receptors on the tumor cell surface.…”