Skip Navigation


Carcinogenesis Advance Access originally published online on October 4, 2007
Carcinogenesis 2008 29(3):466-472; doi:10.1093/carcin/bgm212
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/3/466    most recent
bgm212v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Simpkins, F. A.
Right arrow Articles by Kohn, E. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Simpkins, F. A.
Right arrow Articles by Kohn, E. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.