Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy

Abstract

The mammalian subtilisin/kexin-like proprotein convertase (PC) family has been implicated in the activation of a wide spectrum of proteins. These proteins are usually synthesized as inactive precursors before their conversion to fully mature bioactive forms. A large majority of these active proteins such as matrix metalloproteases, growth factors, and adhesion molecules are crucial in the processes of cellular transformation, acquisition of the tumorigenic phenotype, and metastases formation. Inhibition of PCs significantly affects the malignant phenotype of various tumor cells. In addition to direct tumor cell proliferation and migration blockade, PC inhibitors can also be used to target tumor angiogenesis. In this Review article we discuss a number of recent findings on the clinical relevance of PCs in cancer patients, their implication in the regulation of multiple cellular functions that impact on the invasive/metastatic potential of cancer cells. Thus, PC inhibitors may constitute new promising agents for the treatment of multiple tumors and/or in adjuvant therapy to prevent recurrence.

Figure 1.

Pro-MT1-MMP processing. A: Schematic representation of the structural aspects of the human pro-MT1-MMP (63 kd) and its PC-processing sites at the RRPR⁹²↓ and RRKR¹¹¹↓ The mature enzyme (63 kd) can be further autocatalytically cleaved (itrio) into a 45-kd C-terminal form. Shown are the pro-, catalytic (with the HExxH signature), and hemopexin-like domains. B: Western blots of the cell lysates obtained from the colon carcinoma cell line HT-29 transfected with pIRES2-EGFP vector alone (HT-29) or a recombinant vector containing cDNA of α1-PDX (HT-29/PDX) using mouse anti-human MT1-MMP monoclonal antibody (mAb 3319) recognizing the catalytic domain.

Figure 2.

Extent of angiogenesis determined by immunostaining for CD31. The immunohistochemical analysis were performed on tissue obtained from control tumors (HT-29) or tumors developed from HT-29 cells expressing α1-PDX c-DNA (HT-29/PDX).

Figure 3.

Inhibition of the proteolytic processing of IGF-1R by PC prosegments. A: Schematic representation of the primary structure of human IGF-1R. The positions of its signal peptide (SP), PC-processing site (RKRR), and transmembrane domain (TMD) as well as the α- and β-subunits are shown. B: IGF-1R processing was analyzed by Western blotting of cell lysates obtained from transiently transfected HK293 cells with IGR-1R cDNA together with either the pIRES2-EGFP vector alone (control, CTL) or a recombinant vector containing either profurin, pro-PC5, or pro-PC7 cDNA. Cells expressing α1-PDX are shown for comparison. Note that the inhibitors specifically inhibit the processing of the trans Golgi network form of pro-IGF-1R (210 kd) and not the endoplasmic reticulum-form (200 kd) into the 100-kd β-chain. Also note that the prosegment inhibitor mutated at its secondary cleavage site (m) (148) is as effective as the wild-type inhibitor and that pro-PC7 does not inhibit processing.

Figure 4.

Schematic representation of cascade events implicating PCs for tumor growth and metastasis. By activating GFs, cytokines, and their receptors (GFRs), PCs control tumor cell proliferation and growth. By activating or inducing adhesion molecules convertases modulate adhesion, invasion, and migration of tumor cells and subsequently metastases formation. Arrows indicate the potential sites for PCs inhibitors.