The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells.
Alarm anti-proteases are secreted locally in response to inflammation and have been shown to be elevated in cancers. Secretory leukocyte protease inhibitor (SLPI), an alarm anti-protease, is amplified in ovarian carcinoma and is induced and binds to and protects progranulin (prgn) in inflammation. We reported prgn is a survival protein in ovarian cancer and now hypothesize that SLPI/prgn would promote proliferation and survival. Neutralizing anti-SLPI antibody treatment of HEY-A8 and OVCAR3 ovarian cancer cells decreased cell number (P < 0.001), induced apoptosis and reduced prgn quantity. This was confirmed using SLPI small interfering RNA. Prgn and SLPI were co-immunoprecipitated and co-localized by confocal microscopy. Prgn is a substrate of the serine protease elastase and SLPI is an inhibitor of elastase. Elastase reduced prgn expression, inhibited proliferation in a dose-dependent manner (P </= 0.01) and was pro-apoptotic. SLPI protected prgn from elastase-mediated degradation and restored its survival and proliferative function (P </= 0.04). SLPI also reversed elastase's pro-apoptotic effects (P </= 0.03), yielding recovery of S-phase fraction (P </= 0.001) and increased cyclin D1. Treatment with a general serine protease inhibitor increased prgn, but did not reverse elastase-mediated prgn loss or apoptosis. These data demonstrate that inappropriate over-expression of the alarm anti-protease, SLPI, creates a pro-survival milieu for ovarian cancer.
Simpkins
Fiona A
FA
Molecular Signaling Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Devoogdt
Nick M
NM
Rasool
Nabila
N
Tchabo
Nana E
NE
Alejandro
Emilyn U
EU
Kamrava
Mitchell M R N
MM
Kohn
Elise C
EC
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D017077:Culture Media, Conditioned; D005260:Female; D020868:Gene Silencing; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009500:Neutralization Tests; D010051:Ovarian Neoplasms / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D017077:Culture Media, Conditioned; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D053481:Secretory Leukocyte Peptidase Inhibitor