Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression.
Neutral endopeptidase 24.11 (NEP) is a cell-surface enzyme expressed by prostatic epithelial cells that cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). We report that NEP expression and catalytic activity are lost in vitro in androgen-independent but not androgen-dependent PC cell lines. In vivo, NEP protein expression is commonly decreased in cancer cells of metastatic PC specimens from patients with androgen-independent but not androgen-dependent PC. Overexpression of NEP in androgen-independent PC cells or incubation with recombinant NEP inhibits PC cell growth. Furthermore, in androgen-dependent PC cells, expression of NEP is transcriptionally regulated by androgen and decreases with androgen withdrawal. These data suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by the elimination of androgens, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use mitogenic neuropeptides as an alternate source to androgen in order to stimulate cell proliferation.
Papandreou
C N
CN
Genitourinary Oncology Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Usmani
B
B
Geng
Y
Y
Bogenrieder
T
T
Freeman
R
R
Wilk
S
S
Finstad
C L
CL
Reuter
V E
VE
Powell
C T
CT
Scheinberg
D
D
Magill
C
C
Scher
H I
HI
Albino
A P
AP
Nanus
D M
DM
D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D018450:Disease Progression; D018014:Gene Transfer Techniques; D006801:Humans; D007700:Kinetics; D008297:Male; D009362:Neoplasm Metastasis; D015260:Neprilysin / Q000032:analysis / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D011994:Recombinant Proteins; D013196:Dihydrotestosterone; D015260:Neprilysin; D013752:Tetracycline