This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mercapide, J. Articles by Klein-Szanto, A. J. P. Search for Related Content PubMed PubMed Citation Articles by Mercapide, J. Articles by Klein-Szanto, A. J. P.

Inhibition of Furin-mediated Processing Results in Suppression of Astrocytoma Cell Growth and Invasiveness¹

Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [J. M., R. L. D. C., D. E. B., A. J. P. K-S.]; Departamento de Genética, Universidad de Navarra, Pamplona, Spain 31080 [J. S. C.]; and The Vollum Institute, Oregon Health Sciences Center, Portland, Oregon 97201 [G. T.]

Purpose: Astrocytoma arises in the central nervous system as a tumorof great lethality, in part because of the invasive potential of the neoplastic cells that are able to release extracellular matrix-degrading enzymes. Furin convertase activates several precursor matrix metalloproteases involved in the breakdown of the extracellular matrix. In the present study inhibition of furin was achieved by gene transfer of ₁-antitrypsin Portland (PDX) cDNA.

Experimental Design: This furin inhibitor was transfected into two tumorigenic astrocytoma cell lines. The inhibitory effect was evaluated using in vivo tumorigenicity, invasion, and proliferation assays, as well as by investigating impairment of furin substrate processing.

Results: Expression of PDX prevented the s.c. growth of the transfected cells. Invasion assays demonstrated that PDX-transfected cells exhibited a reduced invasive ability in vitro and in vivo. Furthermore, s.c. growth of PDX transfectant xenotransplants showed a significant reduction in size that coincided with a significant decrease of the in vitro doubling time and of the in vivo cell proliferation ability. Additional studies showed that the furin substrates insulin-like growth factor IR, transforming growth factor ß and membrane type 1-matrix metalloprotease were not activated in PDX-expressing astrocytoma cells.

Conclusions: PDX expression in astrocytoma cells demonstrated a direct mechanistic link between furin inhibition, and decreased astrocytoma proliferation and invasive ability. Because furin inhibition inhibits both invasiveness and cell growth in astrocytoma, furin should be considered a promising target for glioblastoma therapy.

This article has been cited by other articles:

				T. F. Liu, J. Cai, D. M. Gibo, and W. Debinski Reoxygenation of Hypoxic Glioblastoma Multiforme Cells Potentiates the Killing Effect of an Interleukin-13-Based Cytotoxin Clin. Cancer Res., January 1, 2009; 15(1): 160 - 168. [Abstract] [Full Text] [PDF]

				A. A. Samani, S. Yakar, D. LeRoith, and P. Brodt The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights Endocr. Rev., February 1, 2007; 28(1): 20 - 47. [Abstract] [Full Text] [PDF]

				M. Fugere, J. Appel, R. A. Houghten, I. Lindberg, and R. Day Short Polybasic Peptide Sequences Are Potent Inhibitors of PC5/6 and PC7: Use of Positional Scanning-Synthetic Peptide Combinatorial Libraries as a Tool for the Optimization of Inhibitory Sequences Mol. Pharmacol., January 1, 2007; 71(1): 323 - 332. [Abstract] [Full Text] [PDF]

				D. E. Bassi, R. Lopez De Cicco, J. Cenna, S. Litwin, E. Cukierman, and A. J.P. Klein-Szanto PACE4 Expression in Mouse Basal Keratinocytes Results in Basement Membrane Disruption and Acceleration of Tumor Progression Cancer Res., August 15, 2005; 65(16): 7310 - 7319. [Abstract] [Full Text] [PDF]

				R. Lopez de Cicco, D. E. Bassi, S. Zucker, N. G. Seidah, and A. J.P. Klein-Szanto Human Carcinoma Cell Growth and Invasiveness Is Impaired by the Propeptide of the Ubiquitous Proprotein Convertase Furin Cancer Res., May 15, 2005; 65(10): 4162 - 4171. [Abstract] [Full Text] [PDF]

				W. Debinski and D. M. Gibo Fos-Related Antigen 1 Modulates Malignant Features of Glioma Cells Mol. Cancer Res., April 1, 2005; 3(4): 237 - 249. [Abstract] [Full Text] [PDF]

				S. McMahon, F. Grondin, P. P. McDonald, D. E. Richard, and C. M. Dubois Hypoxia-enhanced Expression of the Proprotein Convertase Furin Is Mediated by Hypoxia-inducible Factor-1: IMPACT ON THE BIOACTIVATION OF PROPROTEINS J. Biol. Chem., February 25, 2005; 280(8): 6561 - 6569. [Abstract] [Full Text] [PDF]

				R. L. de Cicco, J. C. Watson, D. E. Bassi, S. Litwin, and A. J. Klein-Szanto Simultaneous Expression of Furin and Vascular Endothelial Growth Factor in Human Oral Tongue Squamous Cell Carcinoma Progression Clin. Cancer Res., July 1, 2004; 10(13): 4480 - 4488. [Abstract] [Full Text] [PDF]

				M. Nejjari, V. Berthet, V. Rigot, S. Laforest, M.-F. Jacquier, N. G. Seidah, L. Remy, E. Bruyneel, J.-Y. Scoazec, J. Marvaldi, et al. Inhibition of Proprotein Convertases Enhances Cell Migration and Metastases Development of Human Colon Carcinoma Cells in a Rat Model Am. J. Pathol., June 1, 2004; 164(6): 1925 - 1933. [Abstract] [Full Text] [PDF]

				N. A. TAYLOR, W. J. M. VAN DE VEN, and J. W. M. CREEMERS Curbing activation: proprotein convertases in homeostasis and pathology FASEB J, July 1, 2003; 17(10): 1215 - 1227. [Abstract] [Full Text] [PDF]

				D. E. Bassi, H. Mahloogi, R. Lopez De Cicco, and A. Klein-Szanto Increased Furin Activity Enhances the Malignant Phenotype of Human Head and Neck Cancer Cells Am. J. Pathol., February 1, 2003; 162(2): 439 - 447. [Abstract] [Full Text] [PDF]