The role of proprotein convertases in cancer

Cancer is a leading cause of death worldwide and accounts for about one fifth of all death in the Western world. In 2008, nearly 12.7 million new cancer cases and 7.6 million cancer deaths occurred worldwide. The development of cancer is a multistage process, during which cells acquire a series of mutations that eventually lead to unrestrained cell growth, evasion of cell death, angiogenesis, invasion of the surrounding tissue and finally spreading to other parts of the body. The mammalian proprotein convertases (PCs) constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin. They have been associated with cancer since the early 1990s. By processing cancer-associated factors, PCs are believed to play key roles in almost every step of cancer development. Seven of these PCs (PC1, PC2, furin, PC4, PC5/6, PACE4 and PC7) activate, or less frequently inactivate, a wide variety of substrates, including hormones, growth factors, receptors, adhesion molecules, angiogenic factors, metalloproteases. Among these substrates, some of them are key factors controlling cancer progression and metastasis. The last member of this family proprotein convertase subtilisin kexin 9 (PCSK9) only cleaves itself and participates in maintaining the levels of cholesterol, which was shown to have impacts on cancer incidence.In this thesis, I focused on the role of two PCs, PC5/6 and PCSK9, in cancer development. I first showed that PC5/6 is systematically down-regulated in human and mice intestinal tumors. In ApcMin/+ mice which are a colonic cancer model and develop numerous adenocarcinomas along the intestinal tract, the specific knockout of PC5/6 in the intestine and colon leads to higher number of tumors, particularly in duodenum. This suggests that PC5/6 plays a protective role against tumorigenesis in the intestine. Although PC5/6 is protective in intestinal cancer, it has been shown to promote tumor progression in other cancer types e.g., brain and skin. Interestingly, PC5/6 is inhibited by some natural inhibitors, the latent TGFbeta binding proteins 2 and 3 (LTBP-2, -3). These two proteins reduce the enzymatic activity of PC5/6A and reduce the bio-availability of PC5/6A by sequestering the zymogen proPC5/6 in the extracellular matrix. Finally, I demonstrated that the lack of PCSK9 leads to a significantly lower level of liver metastasis of melanoma cells. This cancer protective effect is due to low plasma cholesterol levels as well as high apoptosis in liver stroma and metastasized tumors that are associated with PCSK9 deficiency.In summary, the present cumulative data define some of the in vivo roles of PC5/6 and PCSK9 in cancer and should enhance our appreciation of the physiological impact of PC inhibition.

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