Bone Marrow X Kinase–Mediated Signal Transduction in Irradiated Vascular Endothelium

Tu, Tingting; Thotala, Dinesh; Geng, Li; Hallahan, Dennis E.; Willey, Christopher D.

doi:10.1158/0008-5472.can-07-5743

Cited by 18 publications

(13 citation statements)

References 47 publications

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“…Using a second approach to assess function of Bmx in HLEC, we used an inhibitor of Bmx, LFM-A13. This drug has been shown to block Bmx signaling in HUVEC at a dose of 30 µmol/L 30. Hence, we used this concentration to pretreat HLECs for 1 hr before the Matrigel assay.…”

Section: Resultsmentioning

confidence: 99%

Functional Analyses of the Bone Marrow Kinase in the X Chromosome in Vascular Endothelial Growth Factor–Induced Lymphangiogenesis

Jones

Zhang

et al. 2010

ATVB

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Objective— The goal of this study was to investigate the novel hypothesis that bone marrow kinase in the X chromosome (Bmx), an established inflammatory mediator of pathological angiogenesis, promotes lymphangiogenesis. Methods and Results— We have recently demonstrated a critical role for Bmx in inflammatory angiogenesis. However, the role of Bmx in lymphangiogenesis has not been investigated. Here, we show that in wild-type mice, Bmx is upregulated in lymphatic vessels in response to vascular endothelial growth factor (VEGF). In comparison with wild-type mice, Bmx-deficient mice mount weaker lymphangiogenic responses to VEGF-A and VEGF-C in 2 mouse models. In vitro, Bmx is expressed in cultured human dermal microvascular lymphatic endothelial cells. Furthermore, pharmacological inhibition and short interfering RNA mediated silencing of Bmx reduces VEGF-A and VEGF-C-induced signaling and lymphatic endothelial cell tube formation. Mechanistically, we demonstrated that Bmx differentially regulates VEGFR-2 and VEGFR-3 receptor signaling pathways: Bmx associates with and directly regulates VEGFR-2 activation, whereas Bmx associates with VEGFR-3 and regulates downstream signaling without an effect on the receptor autophosphorylation. Conclusion— Our in vivo and in vitro results provide the first insight into the mechanism by which Bmx mediates VEGF-dependent lymphangiogenic signaling.

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Section: Resultsmentioning

confidence: 99%

Functional Analyses of the Bone Marrow Kinase in the X Chromosome in Vascular Endothelial Growth Factor–Induced Lymphangiogenesis

Jones

Zhang

et al. 2010

ATVB

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“…The inclusion of an invasive element may account for the observed differences between the two studies. Indeed, a recent study showed some significant inhibition of HUVEC sprouting on a Matrigel bed (34). The combination of TW-37 (0.5 μM) and radiation (1 Gy) significantly inhibited endothelial cell sprouting compared to either treatment alone.…”

Section: Discussionmentioning

confidence: 99%

Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

Zeitlin

Spalding

Campos

et al. 2010

International Journal of Radiation Oncology*Biology*Physics

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Purpose To investigate the effect of a metronomic (low dose, high frequency) small molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and materials Primary human dermal microvascular endothelial cells (HDMEC) were exposed to ionizing radiation and/or TW-37, and colony formation as well as capillary sprouting in 3-D collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by co-transplantation of human squamous cell carcinoma cells (OSCC3) and HDMEC seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results Low dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low dose TW-37 or radiation partially inhibited endothelial cell sprout formation, while in combination these therapies abrogated new sprouting. Combination of metronomic TW-37 and low dose radiation inhibited tumor growth and resulted in significant increase in time to failure as compared to controls, whereas single agents did not. Notably, histopathological analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions These results demonstrate that metronomic TW-37 potentiates the anti-tumor effects of radiotherapy, and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.

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“…Following cold lysis buffer washes (n=3), 4X SDS sample buffer was added and then boiled for 10 min. This was then run on SDS-PAGE with anti-PY20HRP immunoblotting according as described before [24]. …”

Section: Methodsmentioning

confidence: 99%

Kinomic profiling approach identifies Trk as a novel radiation modulator

Jarboe

Jaboin

Anderson

et al. 2012

Radiotherapy and Oncology

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Background Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches. Materials and methods In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC). Results We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of one hour. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2–15 minutes following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement. Conclusions Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gambogic amide produced radiation sensitization.

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Bone Marrow X Kinase–Mediated Signal Transduction in Irradiated Vascular Endothelium

Cited by 18 publications

References 47 publications

Functional Analyses of the Bone Marrow Kinase in the X Chromosome in Vascular Endothelial Growth Factor–Induced Lymphangiogenesis

Functional Analyses of the Bone Marrow Kinase in the X Chromosome in Vascular Endothelial Growth Factor–Induced Lymphangiogenesis

Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

Kinomic profiling approach identifies Trk as a novel radiation modulator

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