Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Kaltschmidt, Barbara; Witte, Kaya E.; Greiner, Johannes F. W.; Weißinger, Florian; Kaltschmidt, Christian

doi:10.3390/biomedicines10020261

Cited by 19 publications

(13 citation statements)

References 102 publications

(121 reference statements)

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“…Chronic inflammation is known to develop in the tumor microenvironment, which can help malignantly transformed cells to avoid the death that is mediated by factors of the immune system and the action of anticancer drugs [ 12 , 14 , 15 ]. It is known also that the increase and/or emergence of drug resistance in tumor cells may be accompanied by the activation of signaling pathways that are associated with the inflammatory response [ 42 , 60 , 61 , 62 , 63 , 64 ], which is consistent with the results of our work. Our data suggest a high cell culture density of tumor cells as a cause of the pro-inflammatory change in their microenvironment and increase in their drug resistance.…”

Section: Discussionsupporting

confidence: 93%

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

Kobyakova

Lomovskaya

Сенотов

et al. 2022

IJMS

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It is known that cell culture density can modulate the drug resistance of acute myeloid leukemia (AML) cells. In this work, we studied the drug sensitivity of AML cells in high-density cell cultures (cell lines THP-1, HL-60, MV4-11, and U937). It was shown that the AML cells in high-density cell cultures in vitro were significantly more resistant to DNA-damaging drugs and recombinant ligand izTRAIL than those in low-density cell cultures. To elucidate the mechanism of the increased drug resistance of AML cells in high-density cell cultures, we studied the activation of Bcl-2, Hif-1alpha, and NF-kB proteins, as well as cytokine secretion, the inflammatory immunophenotype, and the transcriptome for THP-1 cells in the low-density and high-density cultures. The results indicated that the increase in the drug resistance of proliferating THP-1 cells in high-density cell cultures was associated with the accumulation of inflammatory cytokines in extracellular medium, and the formation of NF-kB-dependent inflammatory-like cell activation with the anti-apoptotic proteins Bcl-2 and Bcl-xl. The increased drug resistance of THP-1 cells in high-density cultures can be reduced by ABT-737, an inhibitor of Bcl-2 family proteins, and by inhibitors of NF-kB. The results suggest a mechanism for increasing the drug resistance of AML cells in the bone marrow and are of interest for developing a strategy to suppress this resistance.

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Section: Discussionsupporting

confidence: 93%

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

Kobyakova

Lomovskaya

Сенотов

et al. 2022

IJMS

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“…Accompanied by the phosphorylation of IκB , NF-κB detaches from IκB and translocates into the nucleus. NF-κB transforms to p-NF-κB in the nucleus and contributes to PDAC proliferation and metastasis [27]. TNFR2 is highly expressed in PDAC tissues and is stimulated by elevated TNF in the TME.…”

Section: Discussionmentioning

confidence: 99%

TNFR2 mediates pancreatic cancer proliferation, migration, and invasion via the NF‑κB signaling pathway

Gao

Zhang

Chen

et al. 2023

Preprint

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant disease with low overall survival; chemotherapy and immunotherapy have limited efficacy. Tumor necrosis factor receptor 2 (TNFR2) contributes to the development and progression of several tumors. In this study, we investigated the clinicopathologic data and outcomes of pancreatic cancer patients and elucidated the molecular mechanisms of TNFR2. Method: We used The Cancer Genome Atlas and the Genotype-Tissue Expression database to compare the expression of the TNFR2 gene between normal (n = 171) and malignant (n = 179) pancreatic tissue. Using immunohistochemical staining, we divided the patients into high and low-expression groups, then investigated clinicopathologic data and survival curves of pancreatic cancer patients. We measured TNFR2 protein expression in PANC-1 and ASPC-1 pancreatic cancer cells subjected to TNFR2 small interfering RNA or negative control treatment. We performed proliferation, invasion, and migration assays to study the biological effects of TNFR2 in PDAC. The molecular mechanisms were validated using western blotting. Results: TNFR2 was more highly expressed in PDAC cells and tissues than in controls. Abundant expression of TNFR2 was associated with aggressive clinicopathologic characteristics and poor outcomes. Overexpression of TNFR2 promoted PDAC cell proliferation, migration, and invasion in vitro. Mechanistically, TNFR2 binds to TNF-ɑ and activates the NF-κB signaling pathway. Conclusion: TNFR2 is a prognostic marker that facilitates the proliferation, migration, and invasion of PDAC via the NF‑κB signaling pathway. TNFR2 may become a therapeutic target.

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“…On a mechanistic level, the transcription factor NF-κB is a well-known driver of GBM invasiveness, angiogenesis, and resistance to radiotherapy [ 13 , 14 ]. As we recently reviewed [ 60 ], findings by Bredel and coworkers strongly suggest a mutual exclusion of NFKBIA (IκB-α) deletion or EGFR amplification oncogene [ 61 ]. Here, the canonical NF-κB subunits RELA and c-REL are highly expressed and localized in the cytoplasm of GSCs.…”

Section: Discussionmentioning

confidence: 99%

Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy

Helweg

Storm

Witte

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is the most aggressive and most common malignant brain tumor with poor patient survival despite therapeutic intervention. On the cellular level, GBM comprises a rare population of glioblastoma stem cells (GSCs), driving therapeutic resistance, invasion, and recurrence. GSCs have thus come into the focus of therapeutic strategies, although their targeting remains challenging. In the present study, we took advantage of three GSCs-populations recently established in our lab to investigate key signaling pathways and subsequent therapeutic strategies targeting GSCs. We observed that NF-κB, a crucial transcription factor in GBM progression, was expressed in all CD44+/CD133+/Nestin+-GSC-populations. Exposure to TNFα led to activation of NF-κB-RELA and/or NF-κB-c-REL, depending on the GBM type. GSCs further expressed the proto-oncogene MYC family, with MYChigh GSCs being predominantly located in the tumor spheres (“GROW”-state) while NF-κB-RELAhigh GSCs were migrating out of the sphere (“GO”-state). We efficiently targeted GSCs by the pharmacologic inhibition of NF-κB using PTDC/Bortezomib or inhibition of MYC by KJ-Pyr-9, which significantly reduced GSC-viability, even in comparison to the standard chemotherapeutic drug temozolomide. As an additional cell-therapeutic strategy, we showed that NK cells could kill GSCs. Our findings offer new perspectives for developing efficient patient-specific chemo- and immunotherapy against GBM.

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Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Cited by 19 publications

References 102 publications

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

TNFR2 mediates pancreatic cancer proliferation, migration, and invasion via the NF‑κB signaling pathway

Targeting Key Signaling Pathways in Glioblastoma Stem Cells for the Development of Efficient Chemo- and Immunotherapy

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