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[Cancer Research 63, 3495-3502, July 1, 2003]
© 2003 American Association for Cancer Research

Carcinogenesis

Bombesin Stimulates Nuclear Factor {kappa}B Activation and Expression of Proangiogenic Factors in Prostate Cancer Cells1

Lyuba Levine, Joseph A. Lucci, III, Barbara Pazdrak, Ji-Zhong Cheng, Yan-Shi Guo, Courtney M. Townsend, Jr. and Mark R. Hellmich2

Departments of Obstetrics and Gynecology [L. L., J. A. L.], Surgery [B. P., J-Z. C., Y-S. G., C. M. T., M. R. H.], and Physiology and Biophysics [M. R. H.], The University of Texas Medical Branch, Galveston, Texas 77555

The majority of deaths from prostate cancer occur in patients with androgen-insensitive metastatic disease. An important early event in the development of the metastatic phenotype is the induction of genes that promote angiogenesis, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), which are released from tumor cells into their microenvironment. Coincident with progression from prostatic carcinoma in situ to metastatic disease is an increase in the number of tumor cells exhibiting neuroendocrine (NE) differentiation. NE cells express a variety of peptide hormones, including the bombesin (BBS)-like peptide, gastrin-releasing peptide (GRP), and its cognate receptor, GRP-R. Although there is a strong positive correlation between the degree of NE differentiation and the metastatic potential of prostate cancers, a mechanistic link between increased expression of peptide hormone receptors, such as GRP-R, and proangiogenic gene expression has not been established. Here we report that BBS stimulates nuclear factor {kappa}B (NF{kappa}B) activation and proangiogenic gene expression in the androgen-insensitive prostate cancer cells lines, PC-3 and DU-145. In PC-3 cells, BBS stimulation of GRP-R resulted in the up-regulation of IL-8 and VEGF expression through a NF{kappa}B-dependent pathway. We show that BBS treatment induced inhibitor of NF{kappa}B degradation, NF{kappa}B translocation to the cell nucleus, increased NF{kappa}B binding to its DNA consensus sequence, and increased IL-8 and VEGF mRNA expression and protein secretion. Treatment with the proteasome inhibitor, MG-132, blocked BBS-stimulated NF{kappa}B DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NF{kappa}B-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NF{kappa}B-dependent up-regulation of proangiogenic gene expression, and suggest a possible molecular mechanism linking NE differentiation and the increased metastatic potential of androgen-insensitive prostate cancers.




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Copyright © 2003 by the American Association for Cancer Research.