Inhibition of proprotein convertases: Approaches to block squamous carcinoma development and progression

Department of Pathology and Tumor Cell Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 08/2007; 46(8):654-9. DOI: 10.1002/mc.20331
Source: PubMed


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.

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    • "These substrates have considerable influence on the development of the neoplastic cell phenotype [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]. Numerous studieshavehighlightedtheroleofPC1,PC2,furin,PC5,PACE4, and PC7 in regulating the biologic behavior of tumors [25] [26] [27] [28] [29] [30]. Many focused on furin, a ubiquitously expressed type I membranebound proteinase, e.g., our laboratory has reported that this PC is implicated in human squamous epithelial cancer cells of different origins [31] [32] [33] [34]. "
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    ABSTRACT: The proprotein convertases (PCs) furin and PACE4 process numerous substrates involved in tumor growth, invasion, and metastasis. We have previously shown that PCs increase the susceptibility to chemical skin carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human skin cancer, we investigated whether or not transgenic mice overexpressing either furin alone or both furin and PACE4 show increased susceptibility to UV carcinogenesis. After backcrossing our previously described furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on tumor incidence/multiplicity but did enhance the tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single furin transgenic mice that was not substantially enhanced in the double furin/PACE4 transgenic mice.
    Neoplasia (New York, N.Y.) 02/2013; 15(2):169-79. DOI:10.1593/neo.121846 · 4.25 Impact Factor
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    • "Some of the PC protein substrates such as growth factors and their cognate receptors, metalloproteinases, and adhesion molecules are highly relevant to the neoplastic cell behavior [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]; therefore, many attempts were made to explore the involvement of PCs in tumor growth and development. Several studies demonstrated that PC1, PC2, furin, PC5, PACE4, and PC7 are involved in regulating the biologic behavior of various types of tumors [19] [20] [21] [22]. Specifically, furin, a ubiquitously expressed type I membrane-bound proteinase, has been reported to be implicated in tumors of different origins. "
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    ABSTRACT: Furin, one of the members of the family of proprotein convertases (PCs), ubiquitously expressed as a type I membrane-bound proteinase, activates several proteins that contribute to tumor progression. In vitro studies using cancer cell lines and clinical specimens demonstrated that furin processes important substrates such as insulin-like growth factor 1 receptor (IGF-1R) and transforming growth factor β, leading to increased tumor growth and progression. Despite the numerous studies associating furin with tumor development, its effects in preclinical models has not been comprehensively studied. In this study, we sought to determine the protumorigenic role of furin in vivo after a two-stage chemical carcinogenesis protocol in transgenic mice in which furin expression was targeted to the epidermal basal layer. We found that processing of the PC substrate IGF-1R and the proliferation rate of mouse epidermis was enhanced in transgenic mice when compared with their WT counterparts. Histopathologic diagnoses of the tumors demonstrated that furin transgenic mice (line F47) developed twice as many squamous carcinomas as the control, WT mice (P < .002). Similarly, tumors cells from transgenic mice were able to process PC substrates more efficiently than tumor cells from WT mice. Furthermore, furin expression resulted in a higher SCC volume in transgenic mice as well as an increase in the percentage of high-grade SCC, including poorly differentiated and spindle cell carcinomas. In conclusion, expression of furin in the basal layer of the epidermis increased tumor development and enhanced tumor growth, supporting the consideration of furin as a potential target for cancer treatment.
    Neoplasia (New York, N.Y.) 04/2012; 14(4):271-82. DOI:10.1593/neo.12166 · 4.25 Impact Factor
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    • "These acquired capabilities, namely cell proliferation, tissue invasion, and adhesion, are essential for malignant growth and progression. Numerous studies have associated the family of enzymes known as the proprotein convertases (PCs) to cancer [2] [3] [4] [5] [6] [7] [8]. PCs are serine proteases that cleave substrates at R-X-K/R-R↓ motif [9] [10]. "
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    ABSTRACT: Prostate cancer remains the single most prevalent cancer in men. Standard therapies are still limited and include androgen ablation that initially causes tumor regression. However, tumor cells eventually relapse and develop into a hormone-refractory prostate cancer. One of the current challenges in this disease is to define new therapeutic targets, which have been virtually unchanged in the past 30 years. Recent studies have suggested that the family of enzymes known as the proprotein convertases (PCs) is involved in various types of cancers and their progression. The present study examined PC expression in prostate cancer and validates one PC, namely PACE4, as a target. The evidence includes the observed high expression of PACE4 in all different clinical stages of human prostate tumor tissues. Gene silencing studies targeting PACE4 in the DU145 prostate cancer cell line produced cells (cell line 4-2) with slower proliferation rates, reduced clonogenic activity, and inability to grow as xenografts in nude mice. Gene expression and proteomic profiling of the 4-2 cell line reveals an increased expression of known cancer-related genes (e.g., GJA1, CD44, IGFBP6) that are downregulated in prostate cancer. Similarly, cancer genes whose expression is decreased in the 4-2 cell line were upregulated in prostate cancer (e.g., MUC1, IL6). The direct role of PACE4 in prostate cancer is most likely through the upregulated processing of growth factors or through the aberrant processing of growth factors leading to sustained cancer progression, suggesting that PACE4 holds a central role in prostate cancer.
    Translational oncology 06/2011; 4(3):157-72. DOI:10.1593/tlo.10295 · 2.88 Impact Factor
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