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Books > Science & Mathematics > Biology, life sciences > Biochemistry
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The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis (Paperback)
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The Role of Proprotein Convertases in Animal Models of Skin Carcinogenesis (Paperback)
Series: Colloquium Series on Protein Activation and Cancer
Expected to ship within 10 - 15 working days
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Many proprotein convertases (PC), especially furin and PACE4, are
involved in pathological processes such as viral infection,
inflammation, hypercholesterolemia, and cancer, and have been
postulated as therapeutic targets for some of these diseases. In
this chapter, we review mostly our work using animal models of
squamous cancers that have been induced by chemical or UV
carcinogenesis protocols to highlight the role of PCs in the
development and progression of experimental tumors. After
demonstrating in wild type mice the role of PACE4 in tumor
progression as well as detecting the expression of PACE4 and furin
in human non-melanoma skin cancers, we developed transgenic mice
that over-express either PACE4 or furin in squamous epithelia,
including the epidermis. This was accomplished by targeting the
expression of the corresponding PC by using the promoter of the
bovine keratin 5. Both K5-PACE4 and K5-Furin transgenic mice showed
increased susceptibility to a two-stage carcinogenesis protocol of
chemical carcinogenesis. Similar studies conducted in K5-PACE4 mice
also showed an increased sensitivity to ultraviolet B radiation
carcinogenesis. In most of these experiments, we were able to
demonstrate that compared to the control wild type mice, the
over-expression of the transgene in the epidermis increased the
number of benign and malignant skin tumors and also had an effect
on tumor progression as evidenced by the presence of less
differentiated tumors and more frequent local and distant
metastases in many of the transgenic lines. Interestingly, double
transgenic mice in which PACE4 and furin are targeted to the
epidermis did not show any additive effect, pointing to a probable
in vivo overlap of functions at least in cutaneous tissues. The
tumor-enhancing effects of PACE4 and furin further support their
possible role as therapeutic targets. Furthermore, a proof of
principle for PC inhibition as a therapeutic tool has been
substantiated by an in vivo experiment in which the PC-inhibitor,
decanoyl-RVKRchloromethylketone, was topically administrated to the
skin of wild type and transgenic mice treated with chemical
carcinogenesis protocols, resulting in a significant decrease of
tumor development and progression.
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