Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines

Authors

Elisabeta Karl, University of Michigan School of DentistryFollow
Kristy Anne Warner, University of Michigan School of DentistryFollow
Benjamin David Zeitlin, University of the PacificFollow
Tomoatsu Kaneko, Niigata UniversityFollow
Lindsey Elizabeth Wurtzel, University of Michigan, School of DentistryFollow
Taocong Jin, University of Michigan, School of DentistryFollow
Jia Chang, University of Michigan, School of DentistryFollow
Shaomeng Wang, University of Michigan - Ann ArborFollow
Cun-Yu Wang, UCLA School of DentistryFollow
Robert M. Strieter, University of VirginiaFollow
Gabriel Nunez, University of Michigan, School of MedicineFollow
Jacques E. Nör, University of Michigan School of DentistryFollow

ORCiD

Dr. Benjamin D. Zeitlin: 0000-0003-0110-0188

Department

Biomedical Sciences

Document Type

Article

Publication Title

Cancer Research

ISSN

1538-7445

Volume

65

Issue

12

DOI

10.1158/0008-5472.CAN-05-0140

First Page

5063

Last Page

5069

Publication Date

Summer 6-15-2005

Abstract

Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappa B (NF-kappa B) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappa B down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.

Recommended Citation

Karl, E., Warner, K. A., Zeitlin, B. D., Kaneko, T., Wurtzel, L. E., Jin, T., Chang, J., Wang, S., Wang, C., Strieter, R. M., Nunez, G., & Nör, J. E. (2005). Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines. Cancer Research, 65(12), 5063–5069. DOI: 10.1158/0008-5472.CAN-05-0140
https://scholarlycommons.pacific.edu/dugoni-facarticles/396