Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens.
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.
Granchi
S
S
Department of Clinical Physiopathology, Unit of Andrology, University of Florence, Florence, Italy.
Brocchi
S
S
Bonaccorsi
L
L
Baldi
E
E
Vinci
M C
MC
Forti
G
G
Serio
M
M
Maggi
M
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D015152:Blotting, Northern; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D016207:Cytokines / Q000494:pharmacology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D019334:Endothelin-3 / Q000032:analysis / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000032:analysis / Q000096:biosynthesis; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000728:Androgens; D016207:Cytokines; D019332:Endothelin-1; D019334:Endothelin-3; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004815:Epidermal Growth Factor; C492359:ECEL1 protein, human; D008666:Metalloendopeptidases