Proprotein convertases (PCs) are a group of Ca2+-dependent
serine proteases that have homology to the endoproteases
subtilisin (bacteria) and kexin (yeast). This group is comprised of less than a dozen members, known as
furin/PACE, PC1/PC3, PC2, PC4, PACE4,
PC5/
PC6, PC7/PC8/LPC, SKI/S1P, and NARC-1/PCSK9. Four PCs (
Furin, PACE4,
PC5, and PC7) have been localized to several different tissues and epithelial or
nervous system tumors. PCs activate their cognate substrates by limited proteolysis at the consensus sequence RXR/KR downward arrow. Many PC substrates are well known
cancer-associated
proteins such as
growth factors,
growth factor receptors,
integrins, and matrix
metalloproteases (
MMPs). For example,
IGF-1 and its
receptor, TGF-beta,
VEGF-C, and MT-
MMPs have direct roles in
tumor progression and
metastasis.
Furin, a well-studied member of the PC family, has been associated with enhanced invasion and proliferation in head and neck, breast, and
lung cancer. Conversely, inhibition of PC activity by PDX or several PC pro-segments, resulted in reduced processing of these key
cancer-related substrates in human
squamous cell carcinomas (SCC),
colon adenocarcinoma, and
astrocytoma cell lines. In parallel to these changes in cell proliferation and invasiveness as well as metastatic ability were markedly impaired. By controlling the maturation/activation of key
cancer-associated
proteins, PCs act as "master switches" at different levels during
tumor development and progression. The manifold effects of PCs, influencing
tumor cell proliferation, motility, adhesiveness, and invasiveness, should be exploited by further developing competitive/inhibitory therapeutic strategies that would be able to neutralize simultaneously the most salient
cancer cell properties.