The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis
Geraldine Siegfried, … , Nabil G. Seidah, Abdel-Majid Khatib
Geraldine Siegfried, … , Nabil G. Seidah, Abdel-Majid Khatib
Published June 1, 2003
Citation Information: J Clin Invest. 2003;111(11):1723-1732. https://doi.org/10.1172/JCI17220.
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Article Oncology

The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis

Abstract

The secretory factor VEGF-C has been directly implicated in various physiological processes during embryogenesis and human cancers. However, the importance of the conversion of its precursor proVEGF-C to mature VEGF-C in tumorigenesis, and vessel formation and the identity of the protease(s) that regulate these processes is/are not known. The intracellular processing of proVEGF-C that occurs within the dibasic motif HSIIRR227SL suggests the involvement of the proprotein convertases (PCs) in this process. In addition, furin and VEGF-C were found to be coordinately expressed in adult mouse tissues. Cotransfection of the furin-deficient colon carcinoma cell line LoVo with proVEGF-C and different PC members revealed that furin, PC5, and PC7 are candidate VEGF-C convertases. This finding is consistent with the in vitro digestions of an internally quenched synthetic fluorogenic peptide mimicking the cleavage site of proVEGF-C (220Q-VHSIIRR↓SLP230). The processing of proVEGF-C is blocked by the inhibitory prosegments of furin, PC5, and PACE4, as well as by furin-motif variants of α2-macroglobulin and α1-antitrypsin. Subcutaneous injection of CHO cells stably expressing VEGF-C into nude mice enhanced angiogenesis and lymphangiogenesis, but not tumor growth. In contrast, expression of proVEGF-C obtained following mutation of the cleavage site (HSIIRR227SL to HSIISS227SL) inhibits angiogenesis and lymphangiogenesis as well as tumor growth. Our findings demonstrate the processing of proVEGF-C by PCs and highlight the potential use of PC inhibitors as agents for inhibiting malignancies induced by VEGF-C.

Authors

Geraldine Siegfried, Ajoy Basak, James A. Cromlish, Suzanne Benjannet, Jadwiga Marcinkiewicz, Michel Chrétien, Nabil G. Seidah, Abdel-Majid Khatib

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Endogenous VEGF-C processing by PC-like activity and coexpression of fur...
Endogenous VEGF-C processing by PC-like activity and coexpression of furin and VEGF-C in mouse tissues. (a) Endogenous proVEGF-C processing was analyzed by Western blotting of PC3 cell–conditioned media obtained from cells transiently transfected with either the pIRES2-EGFP empty vectors (Control) or vector expressing α1-antitrypsin, pSKI-1, α1-PDX, p-furin, furin, or PC5. The corresponding percentages of proVEGF-C cleavage calculated from the ratio of band intensities of VEGF-C/(proVEGF-C + VEGF-C) are indicated. (b) Total RNA was extracted from PC3 cells and the indicated tissues and organs, and RT-PCR analysis was performed using primers specific for VEGF-C, furin, and GAPDH (control) under the conditions described in Methods. Results shown are representative of three experiments.