Abstract
Vascular endothelial growth inhibitor (VEGI) is an endogenous inhibitor of endothelial cell growth and a promising candidate for cancer therapy. VEGI is able to inhibit tumor growth by specifically targeting the tumor neovasculature. Increasing the anti-angiogenic potential of this cytokine is of great interest for its therapeutic potential. NF-κB is known to have an integral role in TNF superfamily signaling, acting as a pro-survival factor. A role of VEGI-induced NF-κB activation in endothelial cells has yet to be described. Here we show that suppression of the NF-κB pathway can increase the apoptotic potential of VEGI. We used siRNA to deplete NF-κB or its activator IKK2 from adult bovine aortic endothelial cells. The siRNA treatments diminished VEGI-induced NF-κB activation, evidenced from a reduced extent of NF-κB nuclear translocation and diminished expression of NF-κB-target genes such as interleukins-6 and -1β. The siRNA-treated endothelial cells when exposed to VEGI exhibited a marked decrease in cell viability and a significant increase in apoptosis. These results confirm that VEGI utilizes NF-κB as a pro-survival role factor in endothelial cells. We then examined whether a combination of VEGI with NF-κB inhibitors would constitute a more potential therapeutic regiment. We found that in the presence of the NF-κB inhibitors curcumin or BMS-345541 there was a marked increase in the apoptotic potential of VEGI on endothelial cells. These findings indicate that a combination therapy using VEGI and NF-κB inhibitors could be a potent approach for cancer treatment.
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Abbreviations
- VEGI:
-
Vascular endothelial growth inhibitor
- TNF:
-
Tumor necrosis factor
- NF-κB:
-
Nuclear factor kappa B
- IKK:
-
IκB kinase
- DR3:
-
Death receptor 3
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Acknowledgments
We thank Talal El-Hefnawy and Adam Farkas for their technical assistance.
Sources of funding
This study is supported in part by grants from The National Institute of Health (CA113875 to LYL and CA113270 to SG), The Hillman Foundation (LYL), and Pennsylvania Department of Health (LYL), and The Chinese Ministry of Science and Technology (2009CB918900 to LYL).
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Grimaldo, S., Tian, F. & Li, LY. Sensitization of endothelial cells to VEGI-induced apoptosis by inhibiting the NF-κB pathway. Apoptosis 14, 788–795 (2009). https://doi.org/10.1007/s10495-009-0351-9
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DOI: https://doi.org/10.1007/s10495-009-0351-9