Human Carcinoma Cell Growth and Invasiveness Is Impaired by the Propeptide of the Ubiquitous Proprotein Convertase Furin

Abstract

Furin, a potent proprotein convertase involved in activation of several cancer-related substrates, is synthesized as an inactive zymogen, thus minimizing the occurrence of premature enzymatic activity that would lead to inappropriate protein activation or degradation. This natural inhibitory mechanism is based on the presence of an inactivating prosegment at the NH 2 terminal of the zymogen. After initial autocatalytic cleavage, the prosegment remains tightly associated with the convertase until it reaches the trans-Golgi network where the dissociation of the prosegment and activation of furin occurs. We hypothesized that the inhibitory properties of the preprosegment of furin (ppFur) could be beneficial if ectopically expressed in tumor cells. Transfection of four human head and neck squamous cell carcinoma cell lines with the complete ppFur cDNA sequence (pIRES-EGFP-ppFur) or with the empty expression vector (pIRES-EGFP) was done. The inhibitory effect was evaluated using in vivo tumorigenicity, invasion, anchorage-independent growth in soft agar, and proliferation assays, as well as by investigating impairment of furin substrates processing. Following transfection of ppFur, a significant reduction in cell proliferation, tumorigenicity, and invasiveness was observed in vitro and in vivo. These biological changes are directly related to the inhibition of furin-mediated activation of crucial cancer-related substrates, such as membrane type 1 matrix metalloproteinase, transforming growth factor-B, insulin-like growth factor-1 receptor, and vascular endothelial growth factor-C. PpFur expression in head and neck squamous cell carcinoma cell lines showed a mechanistic link between furin inhibition, decreased substrate processing, cell proliferation, and invasive ability. These findings suggest that furin inhibition is a feasible approach to ameliorate and even abolish the malignant phenotype of various malignancies. (Cancer Res 2005; 65(10): 4162-71)

Opposing Function of the Proprotein Convertases Furin and PACE4 on Breast Cancer Cells' Malignant Phenotypes: Role of Tissue Inhibitors of Metalloproteinase-1

“…In contrast, overexpression of ppFurin has thus far consistently resulted in reduced malignant phenotypes of various cancer cells (ref. 18, and the present study). Taken together, our results strongly suggest that regulation of the MMP-9/TIMP-1 ratio by PCs in breast cancer cells may be one of the major factors that control their invasive and metastatic abilities.…”

“…Accordingly, overexpression of Furin has been established in various types of cancers (2,10,14) and has been linked to aggressive behavior in some model systems (14). Using ppFurin cells, Lopez de Cicco et al showed that overexpression of this inhibitor in various head and neck squamous cells induced significant reductions in cell proliferation, tumorigenicity, and invasiveness (18). These changes were directly related to the inhibition of Furin-mediated activation of crucial cancer-related substrates (18).…”

Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells

“…The present study demonstrates the importance of PCs in early and late liver colonization by metastatic colon cancer cells and suggests the potential use of PC inhibitors as new therapeutic agents for liver colorectal metastasis prevention. In certain situations specific inhibition of a single PC may be sufficient and more appropriate, as previously reported for furin, the specific inhibition of which was revealed to abolish the malignant phenotype of various malignancies (55). Evidently, more understanding of the molecular mechanisms of the PC inhibitors by using various in vitro and in vivo models is required before testing their efficacy in human cancers.…”

Role of c-Src inhibitor in the regulation of hepatocarcinoma cell migration

“…Furin activation plays a vital role in tumor process (Lopez de Cicco et al, 2005). Furin inhibitor α1-PDX has been used to block Furin activity and to prevent cancer metastasis in biochemical, cellular and animal studies (Molloy and Thomas, 2001).…”