Proprotein convertases: “Master switches” in the regulation of tumor growth and progression

Abstract

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.

TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma

“…These strategies fall into two classes: direct inhibition of TGF-β (using TGF-β-neutralizing antibodies or TGF-β receptor inhibitors) and interference with downstream signaling (e.g., peroxisome proliferator-activated receptor-γ agonists) (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). In our study, we used two strategies to block TGF-β signaling: (i) in a genetic model, TGF-β signaling was inhibited by stable transfection of tumor cells with a soluble TGF-β receptor (sTβRII), which functions as a "TGF-β trap," competing with TGF-β1 and -β3 for binding to TGF-β receptor ΙΙ; and (ii) in a pharmacologic model, TGF-β signaling was inhibited by a neutralizing antibody that blocks all three isoforms of TGF-β.…”

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

“…For example, H 2 O 2 itself is a poor direct activator of MMP-9, and oxidantmediated MMP-9 activation appears to depend primarily on increases in MMP-9 expression (87,128). Also, the Cys-containing prodomain of TACE (ADAM17) functions primarily as an intramolecular chaperone that prevents TACE degradation and aids in its secretion (129), activation of proTACE occurs primarily intracellularly in a late Golgi compartment by proteolytic removal of the prodomain by furin-like proconvertases (PC) (130), which depends primarily on Ca 2+ signaling and intracellular acidification (131). Since DUOX may largely localize intracellularly in association with the ER, and is capable of promoting transmembrane H + transport (19), DUOX-mediated activation of PC-TACE proteolytic cascades could conceivably involve intracellular and H 2 O 2 -independent mechanisms.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…PCs cleave numerous proteins including prohormones, serum proteins, bacterial toxins, viral glycoproteins, metalloproteinases, growth factors, growth factor receptors, neuropeptides, and adhesion molecules. Consequently, these enzymes are involved in numerous physiologic and pathologic pathways including embryonic development, Alzheimer's disease, cancer, obesity, diabetes, cardiovascular disease, and infectious disease (145,146).…”