The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells.

ABSTRACT

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 elastase-mediated degradation and restored its survival and proliferative function (P elastase's pro-apoptotic effects (P 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.