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Carcinogenesis Advance Access published online on October 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm212
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Published by Oxford University Press 2007.

THE ALARM ANTI-PROTEASE, SECRETORY LEUKOCYTE PROTEASE INHIBITOR, IS A PROLIFERATION AND SURVIVAL FACTOR FOR OVARIAN CANCER CELLS

Fiona Simpkins1, Nick Devoogdt1,2, Nabila Rasool1, Nana Tchabo1, Emilyn Alejandro1, Mitchell Kamrava1,3 and Elise C. Kohn1,{wedge}

1 Molecular Signaling Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892
2 ‘Fonds voor Wetenschappelijk Onderzoek Vlaanderen Fellow, Department Molecular and Cellular Interactions, Vlaams interuniversitair Insituut voor Biotechnologie (VIB), Vrije Universiteit Brussel, Brussels, Belgium
3 M.K. was a Howard Hughes Medical Institute/National Institutes of Health Research Scholar

{wedge} Corresponding Author: Elise C. Kohn, MD, 10 Center Drive MSC 1500, Bethesda, Maryland 20892-1500, Phone: 301-402-2726, Fax: 301-480-5142, Email: ek1b{at}nih.gov

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, binds to and protects progranulin (prgn) in inflammation. We reported prgn is a survival protein in ovarian cancer and now hypothesize SLPI/prgn would promote proliferation and survival. Neutralizing anti-SLPI antibody treatment of HEYA8 and OVCAR3 ovarian cancer cells decreased cell number (p<0.001), induced apoptosis, and reduced prgn quantity. This was confirmed using SLPI siRNA. Prgn and SLPI co-immunoprecipitated and colocalized by confocal microscopy. Prgn is a substrate of and SLPI an inhibitor of the serine protease elastase. Elastase reduced prgn expression, inhibited proliferation in a dose-dependent manner (p≤0.01), and was proapoptotic. SLPI protected prgn from elastase-mediated degradation and restored its survival and proliferative function (p≤0.04). SLPI also reversed elastase's proapoptotic 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 overexpression of the alarm anti-protease, SLPI, creates a pro-survival milieu for ovarian cancer.

Key Words: Secretory leukocyte protease inhibitor (SLPI) • ovarian cancer • survival • apoptosis • progranulin

Received January 31, 2007; revised September 14, 2007; accepted September 15, 2007.


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