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Carcinogenesis Advance Access originally published online on October 4, 2007
Carcinogenesis 2008 29(3):466-472; 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 A. Simpkins1, Nick M. Devoogdt1,2, Nabila Rasool1, Nana E. Tchabo1, Emilyn U. Alejandro1, Mitchell M.R.N. Kamrava1 and Elise C. Kohn1,*

1 Molecular Signaling Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892
2 Fonds voor Wetenschappelijk Onderzoek Vlaanderen Fellow, Department Molecular and Cellular Interactions, Vlaams interuniversitair Insituut voor Biotechnologie, Vrije Universiteit Brussel, Brussels, Belgium

* To whom correspondence should be addressed. Tel: +1 301 402 2726; Fax: +1 301 480 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 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.

Abbreviations: CM, conditioned medium; prgn, progranulin; GAPDH, glyceraldehyde dehydrogenase; siRNA, small interfering RNA; SLPI, secretory leukocyte protease inhibitor; TAME, p-toluene sulfonyl)-L-arginine methyl ester; TNF-{alpha}, tumor necrosis factor-{alpha}; XTT, -3'-[1-(phenylamino-carbonyl)-3-4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate

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


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[Abstract] [Full Text] [PDF]


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