title: Overexpression of protease inhibitor-dead secretory leukocyte protease inhibitor causes more aggressive ovarian cancer in vitro and in vivo.
abstract: The alarm anti-protease secretory leukocyte protease inhibitor (SLPI) is frequently overexpressed in ovarian cancer cells and has been proposed for inclusion in biomarker panels but function remains unclear. We hypothesized that SLPI overexpression promotes ovarian cancer growth and survival. Low SLPI-expressing Hey-A8 ovarian cancer cells were engineered to produce functional (WT) or protease inhibitor-null (PI-) mutant SLPI; lack of PI activity was confirmed by enzymatic assay. WT/SLPI and PI- mutants stimulated significant proliferation and survival of Hey-A8 ovarian cancer cells under basal culture conditions (P < or = 0.02), in soft agar colony number and size (P < or = 0.05), and in anoikis resistance (P < or = 0.005). SLPI protected the ovarian cancer survival factor, progranulin (PRGN), and HEY-A8 cells from degradation and apoptosis due to neutrophil elastase. PI-/SLPI cells had greater protective activity than WT/SLPI cells. HEY-A8 murine xenografts revealed enhanced solid tumor formation, dissemination, and invasion in WT/SLPI and PI-/SLPI mutants. Increased proliferation was demonstrated by Ki-67 staining (P < or = 0.02). Increased secreted PRGN was seen in culture and was also observed by immunohistochemistry in the SLPI transfectant xenografts. This study describes a PI-independent function for SLPI in ovarian cancer growth and dissemination.
authors.affiliation: Molecular Signaling Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1906, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Devoogdt
authors.forename: Nabila
authors.initials: N
authors.lastname: Rasool
authors.forename: Ebony
authors.initials: E
authors.lastname: Hoskins
authors.forename: Fiona
authors.initials: F
authors.lastname: Simpkins
authors.forename: Nana
authors.initials: N
authors.lastname: Tchabo
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000077153:Progranulins; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000378:metabolism*
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D005341:Fibrinolysin