Pegylated kunitz domain inhibitor suppresses hepsin-mediated invasive tumor growth and metastasis.
The transmembrane serine protease hepsin is one of the most highly upregulated genes in prostate cancer. Here, we investigated its tumor-promoting activity by use of a mouse orthotopic prostate cancer model. First, we compared the tumor growth of low hepsin-expressing LnCaP-17 cells with hepsin-overexpressing LnCaP-34 cells. After implantation of cells into the left anterior prostate lobe, LnCaP-34 tumors not only grew faster based on increased serum prostate-specific antigen levels but also metastasized to local lymph nodes and, most remarkably, invaded the contralateral side of the prostate at a rate of 100% compared with only 18% for LnCaP-17 tumors. The increased tumor growth was not due to nonspecific gene expression changes and was not predicted from the unaltered in vitro growth and invasion of LnCaP-34 cells. A likely explanation is that the in vivo effects of hepsin were mediated by specific hepsin substrates present in the tumor stroma. In a second study, mice bearing LnCaP-34 tumors were treated with a PEGylated form of Kunitz domain-1, a potent hepsin active site inhibitor derived from hepatocyte growth factor activator inhibitor-1 (K(i)(app) 0.30 +/- 0.02 nmol/L). Treatment of established tumors with PEGylated Kunitz domain-1 decreased contralateral prostate invasion (46% weight reduction) and lymph node metastasis (50% inhibition). Moreover, serum prostate-specific antigen level remained reduced during the entire treatment period, reaching a maximal reduction of 76% after 5 weeks of dosing. The findings show that hepsin promotes invasive prostate tumor growth and metastasis and suggest that active site-directed hepsin inhibition could be effective in prostate cancer therapy.
Li
Wei
W
Department of Protein Engineering, Genentech, South San Francisco, California 94080, USA.
Wang
Bu-Er
BE
Moran
Paul
P
Lipari
Terry
T
Ganesan
Rajkumar
R
Corpuz
Racquel
R
Ludlam
Mary J C
MJ
Gogineni
Alvin
A
Koeppen
Hartmut
H
Bunting
Stuart
S
Gao
Wei-Qiang
WQ
Kirchhofer
Daniel
D
D000818:Animals; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011092:Polyethylene Glycols / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D011480:Protease Inhibitors; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D011092:Polyethylene Glycols; D012697:Serine Endopeptidases; C055645:hepsin