Bombesin stimulates nuclear factor κB activation and expression of proangiogenic factors in prostate cancer cells

Lyuba Levine, Joseph A. Lucci, Barbara Pazdrak, Ji Zhong Cheng, Yan Shi Guo, Courtney Townsend, Mark Hellmich

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

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 κB (NFκB) 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 NFκB-dependent pathway. We show that BBS treatment induced inhibitor of NFκB degradation, NFκB translocation to the cell nucleus, increased NFκB 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 NFκB DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NFκB-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NFκB-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.

Original languageEnglish (US)
Pages (from-to)3495-3502
Number of pages8
JournalCancer Research
Volume63
Issue number13
StatePublished - Jul 1 2003

Fingerprint

Bombesin
Prostatic Neoplasms
Gastrin-Releasing Peptide
Interleukin-8
Vascular Endothelial Growth Factor A
Androgens
Neuroendocrine Cells
Up-Regulation
Bombesin Receptors
vpr Genes
Umbilicus
Gene Expression
Proteasome Inhibitors
Peptide Receptors
Peptide Hormones
Carcinoma in Situ
Consensus Sequence
Gene Expression Regulation
Cell Nucleus
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bombesin stimulates nuclear factor κB activation and expression of proangiogenic factors in prostate cancer cells. / Levine, Lyuba; Lucci, Joseph A.; Pazdrak, Barbara; Cheng, Ji Zhong; Guo, Yan Shi; Townsend, Courtney; Hellmich, Mark.

In: Cancer Research, Vol. 63, No. 13, 01.07.2003, p. 3495-3502.

Research output: Contribution to journalArticle

Levine, Lyuba ; Lucci, Joseph A. ; Pazdrak, Barbara ; Cheng, Ji Zhong ; Guo, Yan Shi ; Townsend, Courtney ; Hellmich, Mark. / Bombesin stimulates nuclear factor κB activation and expression of proangiogenic factors in prostate cancer cells. In: Cancer Research. 2003 ; Vol. 63, No. 13. pp. 3495-3502.
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AU - Levine, Lyuba

AU - Lucci, Joseph A.

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AB - 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 κB (NFκB) 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 NFκB-dependent pathway. We show that BBS treatment induced inhibitor of NFκB degradation, NFκB translocation to the cell nucleus, increased NFκB 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 NFκB DNA binding, and IL-8 and VEGF expression and secretion. Finally, media collected from PC-3 cell cultures, after BBS treatment, stimulated an NFκB-dependent migration of human umbilical vascular endothelial cells in vitro. Together, our data demonstrate a role for BBS and GRP-R in the NFκB-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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