title: Inhibition of proprotein convertases: approaches to block squamous carcinoma development and progression.
abstract: Most proprotein convertase (PC) inhibitors are compounds that act as competitive inhibitors. All of them contain the general cleavage motif RXK/RR that binds to the PC's active site impairing further interactions with their physiological substrates. The first inhibitors synthesized were the acyl-peptidyl-chloromethyl ketones that bind to the PC's active site through its peptidyl group and are able to transverse the plasma membrane due to the acyl moiety. For instance, one of the members of this family that exhibits reduced toxicity and has been widely used as an effective general PCs inhbitor is the derivative decanoyl-RVKR-chloromethylketone (CMK). Another approach to PC inhibition is based on proteins that contain either a natural or a bioengineered PC cleavage consensus site. In this context, the bioengineered serpin, alpha-1-antitrypsin Portland (alpha 1-PDX or PDX), proved to be a potent inhibitor of furin, the most studied of the cancer-related PCs. Both PDX and CMK were able to inhibit invasiveness of squamous cell carcinoma cell lines by blocking activation of cancer-associated PC substrates such as MT-MMPs, IGF-1R, and VEGF-C. A similar effect was produced by inhibiting PC-mediated processing using furin prosegment. PDX and CMK have also been assayed in vivo using skin carcinogenesis models. Newer promising small molecules and RNA interference approaches are also being developed to inhibit PCs.
authors: Department of Pathology and Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors: Ricardo López
authors: RL
authors: de Cicco
authors: Daniel E
authors: DE
authors: Bassi
authors: Fernando
authors: F
authors: Benavides
authors: Claudio J
authors: CJ
authors: Conti
authors: Andrés J P
authors: AJ
authors: Klein-Szanto
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000517:prevention & control*; D049109:Cell Proliferation; D018450:Disease Progression; D006801:Humans; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology / Q000517:prevention & control*
chemical_list: D043484:Proprotein Convertases