Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens.

Abstract

BACKGROUND:

Recent data demonstrate that endothelin-1 (ET-1) concentration increases in plasma of men with advanced, hormone-refractory prostate adenocarcinoma. In addition, ET-1 is involved in osteblastic remodelling and new bone formation, suggesting a role for this vasoactive peptide in the metastatic progression of prostate cancer to the bone.

METHODS:

We investigated the regulation of ET-1 expression in androgen-sensitive and insensitive prostate cancer cell lines by androgens and several factors involved in progression of prostate cancer (EGF) and bone remodelling (TGFbeta-1, IL1-alpha and IGF-1).

RESULTS:

Northern analysis and radio immunoassay demonstrated that all the ET-1 pathways are tuned off in the androgen-sensitive LNCaP cell line when compared to the androgen-insensitive PC-3 and DU145. In PC-3 cells transfected with a full-length androgen receptor expression vector (PC-3-AR), treatment with androgens reduced gene expression and secretion of ET-1 without affecting the gene expression of ET-3. Collectively, these data support a role for androgens in the regulation of ET-1 production by prostate adenocarcinoma cells. In PC-3 and DU145 cells, ET-1 gene expression and secretion were up-regulated by TGFbeta-1, EGF and IL1-alpha, whereas IGF-1 was ineffective. Conversely, none of the treatments affected ECE-1 or ET-3 gene expression.

CONCLUSIONS:

In conclusion, ET-1 production by prostate adenocarcinoma cells is down-regulated by androgens and up-regulated by factors involved in tumour progression indicating a role for this peptide in the biology of prostate cancer. In view of the role exerted by ET-1 in the process of bone metastasis, our data suggest the use of ET-1 receptor antagonists in the treatment of advanced prostate cancer.

• Authors: S Granchi, S Brocchi, L Bonaccorsi, E Baldi, M C Vinci, G Forti, M Serio, M Maggi
• Journal: The Prostate (Prostate) Vol. 49 Issue 4 Pg. 267-77 (Dec 01 2001) ISSN: 0270-4137 [Print] United States
• PMID: 11746273 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2001 Wiley-Liss, Inc.

Chemical References

• Androgens
• Cytokines
• Endothelin-1
• Endothelin-3
• RNA, Messenger
• RNA, Neoplasm
• Epidermal Growth Factor
• ECEL1 protein, human
• Metalloendopeptidases

Topics

• Adenocarcinoma (genetics, metabolism, secondary)
• Androgens (pharmacology, physiology)
• Blotting, Northern
• Bone Neoplasms (genetics, metabolism, secondary)
• Cytokines (pharmacology)
• Endothelin-1 (biosynthesis, genetics)
• Endothelin-3 (analysis, biosynthesis)
• Epidermal Growth Factor (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Metalloendopeptidases (analysis, biosynthesis)
• Neoplasms, Hormone-Dependent (genetics, metabolism, pathology)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Neoplasm (chemistry, isolation & purification)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured