Proliferation of prostate cancer cells and activity of neutral endopeptidase is regulated by bombesin and IL-1beta with IL-1beta acting as a modulator of cellular differentiation.
BACKGROUND
Neutral endopeptidase (NEP) is a cell-surface bound enzyme that cleaves and inactivates neuropeptides such as bombesin and substance P and is involved in the transition from hormonally regulated androgen-dependent prostate cancer (PC) to androgen-independent PC. Neuropeptides are implicated in growth regulation of different cell types and function as transmitters between the neuroendocrine and the immune system.


METHODS
NEP-expression, enzymatic activity of the membrane bound protein, cell proliferation, procalcitonin (PCT) production, and secretion as well as changes in cell morphology of prostatic cells were evaluated after treatment with the immunomodulatory cytokine interleukin-1beta (IL-1beta), neuropeptides (bombesin, substance P), and neuropeptide-conditioned media derived from a human neuroendocrine cell line.


RESULTS
Incubation of LNCaP tumor cells with IL-1beta resulted in a diminished proliferative activity, induction of neurite-like outgrowth which was accompanied by the formation of tubular-type mitochondria typical for neuronal/neuroendocrine cells, and an increased production and secretion of PCT. Conversely, proliferation of prostatic stromal cells was enhanced by the cytokine coming along with an increased number of Golgi-apparatuses and ER-cisternae. Bombesin had an antimitotic effect on LNCaP, but not on stromal cells. Substance P did not influence the growth of any of the cell types investigated, whereas neuropeptide-conditioned media exerted a slightly mitogenic effect on both cell types. The activity of LNCaP cell-surface bound NEP was enhanced by bombesin, but was diminished by substance P and neuropeptide-conditioned media.


CONCLUSIONS
Proliferation and activity of neuropeptide degrading NEP is regulated differently by immunomodulatory substances in PC cells and cells derived from the prostatic stroma with IL-1beta being a potent modulator of cellular differentiation and a potential target for anticancer drug design in PC cells.
Albrecht
Martin
M
Department of Anatomy and Cell Biology, Philipps-University, Marburg, Germany. m.albrecht@lrz.uni-muenchen.de
Doroszewicz
Jolanta
J
Gillen
Sonja
S
Gomes
Iara
I
Wilhelm
Beate
B
Stief
Thomas
T
Aumüller
Gerhard
G
D001839:Bombesin / Q000494:pharmacology*; D002116:Calcitonin / Q000096:biosynthesis / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008854:Microscopy, Electron; D015260:Neprilysin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D011498:Protein Precursors / Q000096:biosynthesis / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells; D013373:Substance P / Q000494:pharmacology
C000606589:CALCA protein, human; D017077:Culture Media, Conditioned; D007375:Interleukin-1; D011498:Protein Precursors; D012333:RNA, Messenger; D013373:Substance P; D002116:Calcitonin; D015260:Neprilysin; D015740:Calcitonin Gene-Related Peptide; D001839:Bombesin