PACE4, a proprotein convertase (PC) studied in our laboratory has a significant role in the processing of metalloproteases and other cancer-related substrates. We have found that PACE4 is overexpressed in high grade murine skin squamous cell carcinomas induced by chemical carcinogenesis protocols. In addition, when overexpressed in mouse skin-derived keratinocytes it is able to increase cell invasiveness. In the present proposal, using transgenic mouse models and chemically-induced skin tumors, we will attempt to prove in vivo, the hypothesis that PCs contribute to tumor development and progression and that in vivo PC inhibition will result in the decrease or absence of skin tumor formation and/or aggressive malignant phenotypes. In addition, we will attempt to demonstrate which of the PC substrates, once activated in vivo, will contribute significantly to the process of tumor growth and progression. The following three aims are to be addressed: 1) Using a transgenic mouse model in which PACE4 is under the control of the keratin 5 promoter (K5-PACE4 mice), chemical carcinogenesis protocols will be used to determine the effect of PACE4 tissue specific overexpression on different stages of skin carcinogenesis. We expect that these transgenic animals will exhibit an increased susceptibility to carcinogenesis. 2) Using the transgenic models, inhibitors of PCs will be evaluated in vivo. We will establish the feasibility of a genetic transfer approach by generating transgenic mice expressing the protein-based PC inhibitor alpha-1 PDX (PDX) in the epidermis. These mice should be resistant to chemical carcinogenesis and/or tumor progression and should neutralize the effects of PACE4. In addition, we will use known PC inhibitors such as chloromethyl ketone, applied topically to the skin of K5-PACE4 mice to evaluate the reversal of the PACE4-induced susceptibility to skin chemical carcinogenesis. 3) In order to determine the critical in vivo PC substrates for cancer development, we propose to cross K5-PACE4 mice with other transgenic animals expressing PACE4 substrates targeted to the skin such as IGF-1, TGF-beta and MT2-MMP. This approach will establish the in vivo hierarchy of the respective substrate activation in the acceleration of skin tumor development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA075028-05
Application #
6579601
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
1999-01-13
Project End
2007-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$359,550
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
073724262
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
Bassi, Daniel E; Cenna, Jonathan; Zhang, Jirong et al. (2015) Enhanced aggressiveness of benzopyrene-induced squamous carcinomas in transgenic mice overexpressing the proprotein convertase PACE4 (PCSK6). Mol Carcinog 54:1122-31
Bassi, Daniel E; Zhang, Jirong; Cenna, Jonathan et al. (2010) Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis. Neoplasia 12:516-26
Page, Robert E; Klein-Szanto, Andres J P; Litwin, Samuel et al. (2007) Increased expression of the pro-protein convertase furin predicts decreased survival in ovarian cancer. Cell Oncol 29:289-99
de Cicco, Ricardo Lopez; Bassi, Daniel E; Benavides, Fernando et al. (2007) Inhibition of proprotein convertases: approaches to block squamous carcinoma development and progression. Mol Carcinog 46:654-9
Lopez de Cicco, Ricardo; Bassi, Daniel E; Zucker, Stanley et al. (2005) Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res 65:4162-71
Bassi, Daniel E; Fu, Jian; Lopez de Cicco, Ricardo et al. (2005) Proprotein convertases: ""master switches"" in the regulation of tumor growth and progression. Mol Carcinog 44:151-61
Bassi, Daniel E; Lopez De Cicco, Ricardo; Cenna, Jonathan et al. (2005) PACE4 expression in mouse basal keratinocytes results in basement membrane disruption and acceleration of tumor progression. Cancer Res 65:7310-9
Lopez de Cicco, Ricardo; Watson, James C; Bassi, Daniel E et al. (2004) Simultaneous expression of furin and vascular endothelial growth factor in human oral tongue squamous cell carcinoma progression. Clin Cancer Res 10:4480-8
Mahloogi, Haleh; Gonzalez-Guerrico, Anatilde M; Lopez De Cicco, Ricardo et al. (2003) Overexpression of the calcium sensor visinin-like protein-1 leads to a cAMP-mediated decrease of in vivo and in vitro growth and invasiveness of squamous cell carcinoma cells. Cancer Res 63:4997-5004
Grille, Sylvia Julien; Bellacosa, Alfonso; Upson, John et al. (2003) The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 63:2172-8

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