Journal Article

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

Fiona A. Simpkins, Nick M. Devoogdt, Nabila Rasool, Nana E. Tchabo, Emilyn U. Alejandro, Mitchell M.R.N. Kamrava and Elise C. Kohn

in Carcinogenesis

Volume 29, issue 3, pages 466-472
Published in print March 2008 | ISSN: 0143-3334
Published online October 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm212
The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells

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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.

Journal Article.  4591 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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