Bombesin stimulates nuclear factor kappa B activation and expression of proangiogenic factors in prostate cancer cells.
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.
Levine
Lyuba
L
Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
Lucci
Joseph A
JA
Pazdrak
Barbara
B
Cheng
Ji-Zhong
JZ
Guo
Yan-Shi
YS
Townsend
Courtney M
CM
Hellmich
Mark R
MR
D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008222:Lymphokines; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001839:Bombesin