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Analysis of Several Pathways for Efficient Killing of Prostate Cancer Stem Cells: A Central Role of NF-κB RELA.

ABSTRACT: Prostate cancer is a common cause of death worldwide. Here, we isolated cancer stem cells (CSCs) from four adenocarcinomas of the prostate (Gleason scores from 3 + 3 up to 4 + 5). CSCs were characterized by the expression of the stem cell markers TWIST, the epithelial cell adhesion molecule (EPCAM), the transcription factors SNAI1 (SNAIL) and SNAI2 (SLUG) and cancer markers such as CD44 and prominin-1 (CD133). All investigated CSC populations contained a fraction highly positive for aldehyde dehydrogenase (ALDH) function and displayed robust expressions of programmed cell death 1 (PD-1) ligands. Furthermore, we investigated immunotherapeutic approaches but had no success even with the clinically used PD-1 inhibitor pembrolizumab. In addition, we studied another death-inducing pathway via interferon gamma signaling and detected high-level upregulations of human leukocyte antigen A (HLA-A) and beta 2-microglobulin (B2M) with only moderate killing efficacy. To examine further killing mechanisms in prostate cancer stem cells (PCSCs), we analyzed NF-κB signaling. Surprisingly, two patient-specific populations of PCSCs were found: one with canonical NF-κB signaling and another one with blunted NF-κB activation, which can be efficiently killed by tumor necrosis factor (TNF). Thus, culturing of PCSCs and analysis of respective NF-κB induction potency after surgery might be a powerful tool for optimizing patient-specific treatment options, such as the use of TNF-inducing chemotherapeutics and/or NF-κB inhibitors.

SUBMITTER: Witte KE

PROVIDER: S-EPMC8396252 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TLR9 signaling through NF-κB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells.

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| S-EPMC4050669 | biostudies-literature

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| S-EPMC10434116 | biostudies-literature

NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis.

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| S-EPMC6652780 | biostudies-literature

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| S-EPMC8640823 | biostudies-literature

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| S-EPMC4670825 | biostudies-literature

NF-κB/RelA controlled A20 limits TRAIL-induced apoptosis in pancreatic cancer.

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| S-EPMC9810737 | biostudies-literature

Differential expression of NF-κB heterodimer RelA/p50 in human urothelial carcinoma.

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| S-EPMC6139250 | biostudies-literature

Modulation of gene expression regulated by the transcription factor NF-κB/RelA.

Project description:Modulators (Ms) are proteins that modify the activity of transcription factors (TFs) and influence expression of their target genes (TGs). To discover modulators of NF-κB/RelA, we first identified 365 NF-κB/RelA-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used a probabilistic model to infer 8349 (M, NF-κB/RelA, TG) triplets and their modes of modulatory action from our combined LC-MS/MS and ChIP-Seq (ChIP followed by next generation sequencing) data, published RelA modulators and TGs, and a compendium of gene expression profiles. Hierarchical clustering of the derived modulatory network revealed functional subnetworks and suggested new pathways modulating RelA transcriptional activity. The modulators with the highest number of TGs and most non-random distribution of action modes (measured by Shannon entropy) are consistent with published reports. Our results provide a repertoire of testable hypotheses for experimental validation. One of the NF-κB/RelA modulators we identified is STAT1. The inferred (STAT1, NF-κB/RelA, TG) triplets were validated by LC-selected reaction monitoring-MS and the results of STAT1 deletion in human fibrosarcoma cells. Overall, we have identified 562 NF-κB/RelA modulators, which are potential drug targets, and clarified mechanisms of achieving NF-κB/RelA multiple functions through modulators. Our approach can be readily applied to other TFs.

| S-EPMC4002100 | biostudies-literature

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