Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation

Rombouts, Caroline; Aerts, An; Quintens, Roel; Baselet, Bjorn; El-Saghire, Hussein; Harms‐Ringdahl, Mats; Haghdoost, Siamak; Janssen, Ann; Michaux, Arlette; Yentrapalli, Ramesh; Benotmane, Mohammed Abderrafi; Oostveldt, Patrick Van; Baatout, Sarah

doi:10.3109/09553002.2014.905724

Cited by 50 publications

(45 citation statements)

References 79 publications

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“…Rombouts et al . reported that a peptide derived from 18 of these 32 amino acids could enter cells21. Therefore, we synthesized an 18-amino acid peptide and tested whether this peptide could inhibit VEGF-A expression in 2774 cells.…”

Section: Resultsmentioning

confidence: 99%

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Hwang

Cho

Lee

et al. 2016

Sci Rep

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Insulin-like growth factor-binding protein 5 (IGFBP-5) plays a role in cell growth, differentiation, and apoptosis. In this study, we found that IGFBP5 was markedly downregulated in ovarian cancer tissue. We investigated the functional significance of IGFBP-5 as a tumor suppressor. To determine functional regions of IGFBP-5, truncation mutants were prepared and were studied the effect on tumor growth. Expression of C-terminal region of IGFBP-5 significantly decreased tumor growth in an ovarian cancer xenograft. A peptide derived from the C-terminus of IGFBP-5 (BP5-C) was synthesized to evaluate the minimal amino acid motif that retained anti-tumorigenic activity and its effect on angiogenesis was studied. BP5-C peptide decreased the expression of VEGF-A and MMP-9, phosphorylation of Akt and ERK, and NF-kB activity, and inhibited angiogenesis in in vitro and ex vivo systems. Furthermore, BP5-C peptide significantly decreased tumor weight and angiogenesis in both ovarian cancer orthotopic xenograft and patient-derived xenograft mice. These results suggest that the C-terminus of IGFBP-5 exerts anti-cancer activity by inhibiting angiogenesis via regulation of the Akt/ERK and NF-kB–VEGF/MMP-9 signaling pathway, and might be considered as a novel angiogenesis inhibitor for the treatment of ovarian cancer.

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Section: Resultsmentioning

confidence: 99%

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Hwang

Cho

Lee

et al. 2016

Sci Rep

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“…of inflammatory adhesion molecules, cytokines, and matrix metalloproteinases, collectively referred to as SASP325. To determine if our treatment with TNFα would also induce components of the SASP, we assessed the endothelial adhesion proteins ICAM-1 and E-selectin, the prothrombotic PAI-1, IGFBP-5, as well as two cytokines IL-6 and IL-8, shown previously to be elevated in endothelial cells at replicative senescence737383940. Levels of ICAM-1, E-selectin, IL-6, and IL-8 in TNFα-treated cells were determined using cell ELISA41 and levels of PAI-1 and IGFBP-5 mRNA were measured using qPCR.…”

Section: Resultsmentioning

confidence: 99%

“…In the present work, we chose to assess the expression of the adhesion molecules E-selectin and ICAM-1, as well as of PAI-1, IGFBP-5, IL-6, and IL-8, previously reported to be upregulated in senescence7373839405253. We found that the expression levels of all of these proteins were elevated after six days of treatment, and with the exception of PAI-1, remained high for at least three further days of cell culturing in normal growth medium, thereby supporting the notion of their senescence.…”

Section: Discussionmentioning

confidence: 99%

Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

Khan

Awad

Oszwald

et al. 2017

Sci Rep

118

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Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.

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“…After a period of 6 weeks, the early stress response along with the associated inflammation led to the induction of premature senescence in the 4.1 mGy/h-exposed samples. This premature senescence was stress-related and showed a possible role of IGF binding protein 5 signalling, known to be involved in the regulation of cellular senescence (166). …”

Section: Molecular and Cellular Mechanisms Underlying The Observedmentioning

confidence: 99%

Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (Review)

Baselet

Rombouts

Benotmane

et al. 2016

International Journal of Molecular Medicine

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118

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Traditionally, non-cancer diseases are not considered as health risks following exposure to low doses of ionizing radiation. Indeed, non-cancer diseases are classified as deterministic tissue reactions, which are characterized by a threshold dose. It is judged that below an absorbed dose of 100 mGy, no clinically relevant tissue damage occurs, forming the basis for the current radiation protection system concerning non-cancer effects. Recent epidemiological findings point, however, to an excess risk of non-cancer diseases following exposure to lower doses of ionizing radiation than was previously thought. The evidence is the most sound for cardiovascular disease (CVD) and cataract. Due to limited statistical power, the dose-risk relationship is undetermined below 0.5 Gy; however, if this relationship proves to be without a threshold, it may have considerable impact on current low-dose health risk estimates. In this review, we describe the CVD risk related to low doses of ionizing radiation, the clinical manifestation and the pathology of radiation-induced CVD, as well as the importance of the endothelium models in CVD research as a way forward to complement the epidemiological data with the underlying biological and molecular mechanisms.

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Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation

Abstract: Our findings motivate further research on the shape of the dose-response and the dose rate effect for radiation-induced vascular senescence.

Cited by 50 publications

References 79 publications

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

The C-terminus of IGFBP-5 suppresses tumor growth by inhibiting angiogenesis

Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

Cardiovascular diseases related to ionizing radiation: The risk of low-dose exposure (Review)

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