title: Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma.
abstract: Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
authors.affiliation: Gray Institute of Radiation Oncology and Biology, University of Oxford, Oxford, United Kingdom.
authors.forename: Chad M
authors.initials: CM
authors.lastname: McKee
authors.forename: Danmei
authors.initials: D
authors.lastname: Xu
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Cao
authors.forename: Sheheryar
authors.initials: S
authors.lastname: Kabraji
authors.forename: Danny
authors.initials: D
authors.lastname: Allen
authors.forename: Veerle
authors.initials: V
authors.lastname: Kersemans
authors.forename: John
authors.initials: J
authors.lastname: Beech
authors.forename: Sean
authors.initials: S
authors.lastname: Smart
authors.forename: Freddie
authors.initials: F
authors.lastname: Hamdy
authors.forename: Adrian
authors.initials: A
authors.lastname: Ishkanian
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.forename: Melania
authors.initials: M
authors.lastname: Pintile
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.forename: Varune Rohan
authors.initials: VR
authors.lastname: Ramnarine
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Chad
authors.initials: C
authors.lastname: Mallof
authors.forename: Wan
authors.initials: W
authors.lastname: Lam
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058258:Serpin E2 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D053823:Hedgehog Proteins; D009363:Neoplasm Proteins; C509239:SHH protein, human; D058258:Serpin E2; C465570:Shh protein, mouse