Cytotoxic activity of a diphtheria toxin/FGF6 mitotoxin on human tumour cell lines

Coll-Fresno, Pedro Miguel; Batoz, M; Tarquin, Sylvie; Birnbaum, Daniel; Coulier, François

doi:10.1038/sj.onc.1200826

Cited by 6 publications

(4 citation statements)

References 28 publications

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“…In addition, the FGF6 protein can be driven by a hydrophobic leader peptide through the endoplasmic reticulum where it becomes glycosylated. [ 39 ] Here, we found that FGF6 knockdown led to the reduced expression of angiogenesis factors (EPO and VEGF) in BC cells and the suppressed migratory ability and angiogenesis of HUVECs, indicating the crucial function of FGF6 in angiogenesis. In addition, aerobic glycolysis inhibitor 2‐DG decreased total branching length and intersection number in both BC cells and HUVECs, suggesting that inhibition of aerobic glycolysis suppresses angiogenesis in BC.…”

Section: Discussionmentioning

confidence: 77%

“…In addition, the FGF6 protein can be driven by a hydrophobic leader peptide through the endoplasmic reticulum where it becomes glycosylated. [39] Here, we found that FGF6 knockdown led to the reduced expression of angiogenesis factors F I G U R E 6 FGF6 promotes BC cell aerobic glycolysis by activating the PI3K/Akt and MAPK signaling pathways. (A) The levels of proteins involved in the PI3K/Akt signaling pathway were examined using Western blot analysis.…”

Section: Discussionmentioning

confidence: 83%

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Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

Zhi

Cai

et al. 2023

J Biochem & Molecular Tox

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Metabolic abnormalities and uncontrolled angiogenesis are two vital features of malignant tumors. Although fibroblast growth factor 6 (FGF6) is known to promote the proliferation and migration of bladder cancer (BC) cells, its influences on aerobic glycolysis and angiogenesis in BC remain unclear. Gene expression at messenger RNA and protein levels were examined by reverse transcription‐quantitative polymerase chain reaction and Western blot analyses, respectively. Lactate production and glucose uptake in BC cells were evaluated by performing aerobic glycolysis assays. A vasculogenic mimicry assay was executed for assessing the angiogenesis of BC cells. The viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs) cocultured with supernatants of BC cells were detected using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, wound healing assay, and tube formation assay. It was found that FGF6 displayed a high level in BC cell lines. Silencing of FGF6 reduced the levels of lactate production, glucose uptake, and the expression of angiogenic factors and glycolytic enzymes in BC cells, which also inhibited the viability and migration of HUVECs. In addition, FGF6 depletion or aerobic glycolysis inhibitor 2‐deoxy‐d‐glucose treatment decreased the total branching length and intersection number of both BC cells and HUVECs. Moreover, glucose or lactate treatment reversed FGF6‐induced suppression of cell viability, migration, tube formation, and vasculogenic mimicry. The activation of the phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (Akt) and mitogen‐activated protein kinase (MAPK) signaling pathways was blocked by silenced FGF6. Furthermore, PI3K/Akt inhibitor (LY2940002) and p38‐MAPK inhibitor (SB203580) inhibited the levels of aerobic glycolysis‐related proteins. In conclusion, FGF6 knockdown suppressed aerobic glycolysis, thereby inhibiting angiogenesis in BC via regulation of the PI3K/Akt and MAPK signaling pathways.

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Section: Discussionmentioning

confidence: 77%

“…In addition, the FGF6 protein can be driven by a hydrophobic leader peptide through the endoplasmic reticulum where it becomes glycosylated. [39] Here, we found that FGF6 knockdown led to the reduced expression of angiogenesis factors F I G U R E 6 FGF6 promotes BC cell aerobic glycolysis by activating the PI3K/Akt and MAPK signaling pathways. (A) The levels of proteins involved in the PI3K/Akt signaling pathway were examined using Western blot analysis.…”

Section: Discussionmentioning

confidence: 83%

Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

Zhi

Cai

et al. 2023

J Biochem & Molecular Tox

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“…It was found that the recombinant fusion toxin was much less active than the chemical conjugate, but both toxins produced antitumour activity in vivo [235,236]. FGF6 has been fused to truncated DT and shown to be cytotoxic to FGFR-bearing cells [237,238].…”

Section: Recombinant Toxins Targeting Fibroblast Growth Factorsmentioning

confidence: 99%

Recombinant toxins in haematologic malignancies and solid tumours

Kreitman

1998

Expert Opinion on Investigational Drugs

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Recombinant toxins constitute a new modality for the treatment of cancer, since they target cells displaying specific surface-receptors or antigens. They are fusion proteins, which contain toxin and ligand regions, and are produced in Escherichia coli. The ligand may be a growth factor or a fragment of an antibody, and the toxin is usually one of the two bacterial toxins: Pseudomonas exotoxin and diphtheria toxin. Compared to the earlier generation chemical conjugates of ligands and toxins, recombinant toxins have many advantages, including homogeneity with respect to the connection between the ligand and toxin, ease and yield of production and small size. A variety of chemotherapy-resistant haematologic and solid tumours have been targeted with recombinant toxins, and clinical trials with many of them have recently demonstrated their effectiveness. Moreover, their unwanted toxic effects are different from those of most chemotherapeutic agents, supporting the expectation that they can be combined with existing modalities to improve the clinical resources available to treat cancer in humans.

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“…Moreover, as the FGF signal pathways play a crucial role in neovascularization, the FGF-based chemotherapeutic delivery agent will compete with circulating FGF for binding to endothelial cells, leading to vascular growth inhibition and tumor cell apoptosis 11. Protein toxins directly conjugated to FGF have been demonstrated to preferentially kill tumor cells in vitro and in vivo 12–15. However, these toxin conjugates have the disadvantages of developing immunogenicity and toxicity.…”

mentioning

confidence: 99%

Dendrimer-based tumor cell targeting of fibroblast growth factor-1

Thomas

Shukla

Kotlyar

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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Fibroblast Growth Factor Receptor (FGFR) is overexpressed in a wide variety of tumors, and therefore is an attractive target for drug delivery. Recombinant FGF-1 was purified and attached to a fifth-generation (G5) polyamidoamine dendrimer. The specific binding and internalization of this conjugate labeled with FITC was demonstrated by flow cytometry as well as by confocal microscopic analysis in cell lines expressing FGFR. The binding and uptake of FGF-conjugated dendrimers was completely blocked by excess non-conjugated FGF-1. Confocal microscopic analysis showed cytosolic as well as nuclear localization. Multivalent G5-FGF nanoparticles may serve as a platform for cytosolic as well as nuclear drug delivery in tumor cells, and as an FGF delivery agent for angiogenesis and wound healing. Our study shows for the first time the applicability of a dendrimer nanodevice for tumor cell targeting through FGFR.The fibroblast growth factors (FGFs) are a family of 23 identified proteins which modulate diverse physiological functions such as cell proliferation, cell migration, wound healing, angiogenesis, and tumorigenesis.1 -6 Their receptors (FGFR1-4), a family of four high affinity receptors, form a ternary membrane complex with an FGF and heparin sulphate. FGF-1 (acidic FGF; FGFα) is a 154-amino acid protein which preferentially binds to FGFR1 and FAFR4 and following internalization with the receptor, it is taken up also into the nuclear compartment.7 , 8 FGFR is known to be overexpressed in cancers such as those of the bladder, breast, prostate, and squamous cells, and the overexpression can lead to tumor cell growth, tumor invasion, and metastasis.1 -6 Although FGFR is also expressed in normal cells, 9 the overexpression of this protein in tumors can be exploited as a therapeutic strategy for tumor-targeted drug delivery. 10 Moreover, as the FGF signal pathways play a crucial role in neovascularization, the FGFbased chemotherapeutic delivery agent will compete with circulating FGF for binding to endothelial cells, leading to vascular growth inhibition and tumor cell apoptosis. 11 Protein toxins directly conjugated to FGF have been demonstrated to preferentially kill tumor cells in vitro and in vivo. [12][13][14][15] However, these toxin conjugates have the disadvantages of developing immunogenicity and toxicity. In this study we report the synthesis and FGFR-dependent tumor cell delivery of a dendrimer-FGF nanodevice. Dendrimer-based targeted delivery of a large payload of drugs through the FGFR will overcome the limitations of a simple `FGF-Toxin' or FGF-Drug' conjugates.© 2009 Elsevier Ltd. All rights reserved Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered...

show abstract

Cytotoxic activity of a diphtheria toxin/FGF6 mitotoxin on human tumour cell lines

Cited by 6 publications

References 28 publications

Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

Silencing of FGF6 hampers aerobic glycolysis and angiogenesis in bladder cancer by regulating PI3K/Akt and MAPK signaling pathways

Recombinant toxins in haematologic malignancies and solid tumours

Dendrimer-based tumor cell targeting of fibroblast growth factor-1

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