A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells

Kaltschmidt, Christian; Banz‐Jansen, Constanze; Benhidjeb, Tahar; Beshay, Morris; Förster, Christine; Greiner, Johannes F. W.; Hamelmann, Eckard; Jorch, Norbert; Mertzlufft, F.; Pfitzenmaier, Jesco; Simon, Matthias; Esch, Jan Schulte am; Wähnert, Dirk; Weißinger, Florian; Wilkens, Ludwig; Kaltschmidt, Barbara

doi:10.3390/cancers11050655

Cited by 90 publications

(65 citation statements)

References 161 publications

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“…NF-κB signaling is known to maintain the characteristics of CSCs associated with cancer progression. After cisplatin treatment, the dormant cells displayed an increased expression of cells with CSCs markers in OC, indicating the resistance of this cell fraction [ 39 ]. Targeting the PTGS2-NF-κB axis in CSCs will provide new insight into OC therapy.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Behera

Ashraf

Srivastava

et al. 2020

Heliyon

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Background Epithelial ovarian cancer (EOC) is a lethal and aggressive gynecological malignancy. Despite recent advances, existing therapies are challenged by a high relapse rate, eventually resulting in disease recurrence and chemoresistance. Emerging evidence indicates that a subpopulation of cells known as cancer stem-like cells (CSLCs) exists with non-tumorigenic cancer cells (non-CSCs) within a bulk tumor and is thought to be responsible for tumor recurrence and drug-resistance. Therefore, identifying the molecular drivers for cancer stem cells (CSCs) is critical for the development of novel therapeutic strategies for the treatment of EOC. Methods Two gene datasets were downloaded from the Gene Expression Omnibus (GEO) database based on our search criteria. Differentially expressed genes (DEGs) in both datasets were obtained by the GEO2R web tool. Based on log 2 (fold change) >2, the top thirteen up-regulated genes and log 2 (fold change) < -1.5 top thirteen down-regulated genes were selected, and the association between their expressions and overall survival was analyzed by OncoLnc web tool. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways analysis, and protein-protein interaction (PPI) networks were performed for all the common DEGs found in both datasets. SK-OV-3 cells were cultured in an adherent culture medium and spheroids were generated in suspension culture with CSCs specific medium. RNA from both cell population was extracted to validate the selected DEGs expression by q-PCR. Growth inhibition assay was performed in SK-OV-3 cells after carboplatin treatment. Results A total of 200 DEGs, 117 up-regulated and 83 down-regulated genes were commonly identified in both datasets. Analysis of pathways and enrichment tests indicated that the extracellular matrix part, cell proliferation, tissue development, and molecular function regulation were enriched in CSCs. Biological pathways such as interferon-alpha/beta signaling, molecules associated with elastic fibers, and synthesis of bile acids and bile salts were significantly enriched in CSCs. Among the top 13 up-regulated and down-regulated genes, MMP1 and PPFIBP1 expression were associated with overall survival. Higher expression of ADM, CXCR4, LGR5, and PTGS2 in carboplatin treated SK-OV-3 cells indicate a potential role in drug resistance. Conclusions The molecular signature and signaling pathways enriched in ovarian CSCs were identified by bioinformatics analysis. This analysis could provide further research ideas to find the new mechanism and novel potential therapeutic targets for ovarian CSCs.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Behera

Ashraf

Srivastava

et al. 2020

Heliyon

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“…STAT3 can be activated by receptor tyrosine kinases such as c-Met in a Janus family kinase-mediated way [25,43]. NF-κB is an ubiquitously expressed transcription factor and a key player in cancer initiation and progression by promoting proliferation of cancer cells and inhibiting cancer cells apoptosis [44]. Recently, it was found that c-Met can activate PI3K/Akt signaling pathway, leading to downstream activation of NF-κB to promote tumor metastasis [26].…”

Section: Discussionmentioning

confidence: 99%

Dictamnine, a Novel c-Met Inhibitor, Suppresses the Proliferation of Lung Cancer Cells by Downregulating the PI3K/Ak/mTOR and MAPK Signaling Pathways

Zhang

Peng

et al. 2020

Preprint

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Background: Dictamnine (Dic), a naturally occurring furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display a wide range of potential pharmacological properties including anticancer activity against multiple cancer types. However, little is known about the direct target proteins and anticancer mechanisms of Dic.Methods: Anticancer effects of Dic and chemotherapy resistance of lung cancer were determined by CCK8, EdU and apoptosis assay. Boyden chamber migration and invasion, wound healing assay, plate colony formation and sphere formation assay were performed to explore the effects of Dic on metastasis and stemness of lung cancer cells. Protein docking analysis, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used for prediction and confirmation of the interaction between Dic and c-Met. qRT-PCR, Western blotting and immunohistochemistry (IHC) were used in mechanism investigation. Tumor xenograft model was used to evaluate the anti-tumor effects of Dic in vivo.Results: Dic was found to suppress the proliferation of lung cancer cells and attenuate the activation of the PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by directly inhibiting the phosphorylation and activation of the receptor tyrosine kinase c-Met. Moreover, Dic treatment significantly inhibited the colony formation, migration, invasion, stemness, adhesive ability, epithelial-mesenchymal transition and in vivo xenograft tumor growth of A549 lung cancer cells. Notably, the combination of Dic and gefitinib synergistically inhibited the cell proliferation, induced apoptosis, and suppressed the PI3K/Akt/mTOR and MAPK signaling pathways in PC9 gefitinib resistant cells.Conclusions: In conclusion, Dic was identified as a novel c-Met inhibitor and our results suggest the potential use of Dic as a new therapeutic agent in the treatment of lung cancer or other cancers with overactive c-Met pathway.

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“…Although some established cellular model lines were derived from primary native tumor tissue [ 7 , 8 , 12 ], such cell lines still lack cancer stem cell characteristics. Cancer stem cells (CSC) are a small subpopulation of tumor cells of high plasticity driving tumor growth, repopulation after injury, and metastasis in a broad range of solid tumors including CRC [ 13 , 14 ]. Next to mediating invasiveness and resistance to chemotherapy, CSC also use immune system escape and are thus crucial mediators of cancer relapse.…”

Section: Introductionmentioning

confidence: 99%

“…Next to mediating invasiveness and resistance to chemotherapy, CSC also use immune system escape and are thus crucial mediators of cancer relapse. Next to in vitro propagation as spheres [ 14 , 15 , 16 , 17 ], cancer stem cell markers like prominin-1 (CD133) and CD44 antigen (CD44) are frequently used to identify cancer stem cells in CRC [ 3 , 6 ]. Important regulators of cancer stem cell characteristics particularly include the members of the MYC transcription factor family, consisting of L-, N-, and CMYC.…”

Section: Introductionmentioning

confidence: 99%

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

Esch

Windmöller

Hanewinkel

et al. 2020

Cancers

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Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.

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A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells

Cited by 90 publications

References 161 publications

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Dictamnine, a Novel c-Met Inhibitor, Suppresses the Proliferation of Lung Cancer Cells by Downregulating the PI3K/Ak/mTOR and MAPK Signaling Pathways

Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

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