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 Tchabo, Emilyn U. Alejandro, Mitchell M.R.N. Kamrava, Elise C. Kohn

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 ≤ 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.

Original languageEnglish (US)
Pages (from-to)466-472
Number of pages7
JournalCarcinogenesis
Volume29
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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Secretory Leukocyte Peptidase Inhibitor
Ovarian Neoplasms
Peptide Hydrolases
Pancreatic Elastase
Apoptosis
Inflammation
Serine Proteinase Inhibitors
Cyclin D1
Serine Proteases
S Phase
Confocal Microscopy
Small Interfering RNA
Cell Count

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Simpkins, F. A., Devoogdt, N. M., Rasool, N., Tchabo, N., Alejandro, E. U., Kamrava, M. M. R. N., & Kohn, E. C. (2008). The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. Carcinogenesis, 29(3), 466-472. https://doi.org/10.1093/carcin/bgm212
Simpkins, Fiona A. ; Devoogdt, Nick M. ; Rasool, Nabila ; Tchabo, Nana ; Alejandro, Emilyn U. ; Kamrava, Mitchell M.R.N. ; Kohn, Elise C. / The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. In: Carcinogenesis. 2008 ; Vol. 29, No. 3. pp. 466-472.
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The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells. / Simpkins, Fiona A.; Devoogdt, Nick M.; Rasool, Nabila; Tchabo, Nana; Alejandro, Emilyn U.; Kamrava, Mitchell M.R.N.; Kohn, Elise C.

In: Carcinogenesis, Vol. 29, No. 3, 01.03.2008, p. 466-472.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The alarm anti-protease, secretory leukocyte protease inhibitor, is a proliferation and survival factor for ovarian cancer cells

AU - Simpkins, Fiona A.

AU - Devoogdt, Nick M.

AU - Rasool, Nabila

AU - Tchabo, Nana

AU - Alejandro, Emilyn U.

AU - Kamrava, Mitchell M.R.N.

AU - Kohn, Elise C.

PY - 2008/3/1

Y1 - 2008/3/1

N2 - 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.

AB - 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.

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U2 - 10.1093/carcin/bgm212

DO - 10.1093/carcin/bgm212

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