Furin-mediated protein processing in infectious diseases and cancer

Braun, Elisabeth; Sauter, Daniel

Furin has been termed a 'master switch of tumor growth and progression' 28,29 as its aberrant expression or activation can promote the formation and progression of various malignancies including colon carcinoma, rhabdomyosarcoma, head and neck cancers, lung, skin and brain tumors. 30 In some cases, furin levels positively correlate with aggressiveness, and increased furin expression has been proposed as prognostic marker for advanced cancers. 30 The oncogenic and prometastatic activity of furin has been ascribed to its ability to activate proteins that promote cell proliferation, angiogenesis, migration and tissue invasion. For example, furin cleaves and activates growth factors such as IGFs, PDGFs or NGF that enhance cell proliferation and consequently tumor growth. Similarly, angiogenic and lymphangiogenic factors such as VEGF-C and VEGF-D may be hyperactivated and promote the vascularisation and growth of solid tumors. 30 Notably, furin expression is induced by hypoxia, as all three FUR promoters harbour binding sites for the hypoxia-inducible factor-1 (HIF-1). 31 Thus, furin-mediated vascularisation may preferentially occur in otherwise growth-restricted hypoxic tumors. Interestingly, hypoxia also results in subcellular relocalisation of furin to the cell surface, which may further enhance processing of growth factors and other extracellular tumorigenic precursor proteins. 32 Besides effects on tumor growth, furin can also promote migration and extravasation of malignant cells as it processes adhesion molecules mediating cell-cell and cell-matrix interactions. The cleavage of integrins may be particularly relevant as they not only mediate adhesion of cells to the extracellular matrix, but also act as signal transducers regulating cell growth, division and survival. 33 In addition, furin activates matrix metalloproteinases (e.g. MMP14) that facilitate metastasis by degrading components of the extracellular matrix. 30 Finally, increased furin activity may also promote cancer development by suppressing protective antitumor mechanisms. For example, increased furin-mediated activation of TGFb reduces immune surveillance by promoting the development of suppressive T reg cells and inhibiting effector T-cell functions. 34 The key role of furin in immunity is highlighted by T-cellspecific furin knock-out mice, which harbour inherently over-reactive effector T cells that secrete reduced levels of active TGFb. 35 Notably, positive feedback loops can further enhance the oncogenic potential of furin. For example, the furin substrate TGFb not only increases furin mRNA expression, but also enhances its proteolytic activity by an unknown mechanism. 36 Similarly, furin enhances the secretion of IFNc, which in turn activates the FUR promoter. 11, 14 This mutual enhancement seems particularly important given the key role of IFNc in tumor development and progression. 37 On the one hand, furin-driven IFNc release may have beneficial effects as it boosts the tumorlytic activity of natural killer cells and cytotoxic T lymphocytes. Furthermore, IFNc may act as an antiangiogenic factor and directly inhibit tumor cell proliferation by inducing the expression of tumor suppressors such as p21 or p27. On the other hand, however, recent evidence suggests that IFNc may also exert tumor-promoting effects, for example by selecting for immune evasive phenotypes and promoting an immunosuppressive tumor microenvironment. 37 Intriguingly, a study on laryngeal cancer pa