title: Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target.
abstract: Proprotein convertases are a family of kexin-like serine proteases that process proteins at single and multiple basic residues. Among the predicted and identified PC substrates, an increasing number of proteins having functions in cancer progression indicate that PCs may be potential targets for antineoplastic drugs. In support of this notion, we identified PACE4 as a vital PC involved in prostate cancer proliferation and progression, contrasting with the other co-expressed PCs. The aim of the present study was to test the importance of PCs in ovarian cancer cell proliferation and tumor progression. Based on tissue-expression profiles, furin, PACE4, PC5/6 and PC7 all displayed increased expression in primary tumor, ascites cells and metastases. These PCs were also expressed in variable levels in three model ovarian cell lines tested, namely SKOV3, CAOV3 and OVCAR3 cells. Since SKOV3 cells closely represented the PC expression profile of ovarian cancer cells, we chose them to test the effects of PC silencing using stable gene-silencing shRNA strategy to generate knockdown SKOV3 cells for each expressed PC. In vitro and in vivo assays confirmed the role of PACE4 in the sustainment of SKOV3 cell proliferation, which was not observed with the other three PCs. We also tested PACE4 peptide inhibitors on all three cell lines and observed consequent reduced cell proliferation which was correlated with PACE4 expression. Overall, these data support a role of PACE4 in promoting cell proliferation in ovarian cancer and provides further evidence for PACE4 as a potential therapeutic target.
authors.affiliation: MALDI Imaging Team, Laboratoire de Spectrométrie de Masse Biologique Fondamentale et Appliquée, Université Nord de France, Cité Scientifique, Université de Lille 1, Villeneuve D'Ascq, France; Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Rémi
authors.initials: R
authors.lastname: Longuespée
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Levesque
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gagnon
authors.affiliation: MALDI Imaging Team, Laboratoire de Spectrométrie de Masse Biologique Fondamentale et Appliquée, Université Nord de France, Cité Scientifique, Université de Lille 1, Villeneuve D'Ascq, France; Laboratory of Clinical Proteomic, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vergara
authors.affiliation: Laboratory of Clinical Proteomic, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy.
authors.forename: Michelle
authors.initials: M
authors.lastname: Maffia
authors.affiliation: MALDI Imaging Team, Laboratoire de Spectrométrie de Masse Biologique Fondamentale et Appliquée, Université Nord de France, Cité Scientifique, Université de Lille 1, Villeneuve D'Ascq, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Fournier
authors.affiliation: MALDI Imaging Team, Laboratoire de Spectrométrie de Masse Biologique Fondamentale et Appliquée, Université Nord de France, Cité Scientifique, Université de Lille 1, Villeneuve D'Ascq, France. Electronic address: michel.salzet@univ-lille1.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Salzet
authors.affiliation: Faculté de Médecine et des Sciences de la Santé, Institut de Pharmacologie de Sherbrooke et Département de chirurgie et service d'urologie, Université de Sherbrooke, Sherbrooke, Canada. Electronic address: robert.day@usherbrooke.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Day
keywords: PACE4; SKOV3 cells; proprotein convertases; xenografts