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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.

SUBMITTER: Khatib AM

PROVIDER: S-EPMC1850825 | biostudies-literature | 2002 Jun

REPOSITORIES: biostudies-literature

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

Khatib Abdel-Majid AM Siegfried Géraldine G Chrétien Michel M Metrakos Peter P Seidah Nabil G NG

The American journal of pathology 20020601 6

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. In ...[more]

PMID: 12057895

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Project description:Proprotein convertases (PCs), also known as eukaryotic subtilases, are a group of serine proteases comprising furin (PACE), PC1 (PC3), PC2, PC4, PACE4, PC5 (PC6), and PC7 (LPC, PC8) that generate bioactive proteins and peptides, such as hormones, receptors, and growth factors by cleaving precursor proteins at multibasic motifs. Two other family members, SKI-1/S1P and PCSK9, cleave regulator proteins involved in cholesterol and fatty acid homeostasis at nonbasic peptide bonds. Furin is ubiquitous in eukaryotic tissues and cells. PACE4, PC5, and PC7 are also widespread, whereas the expression of the other PCs is more restricted. PCs are synthesized as multi-segmented zymogens which are autocatalytically activated. The prodomains have regulatory and inhibitory functions. The catalytic domains are the most conserved domains among the PCs. The architecture of the catalytic active furin domain is known in different binding states. The C-terminal parts of the PCs differ in length and structure and contain encoded peptide signatures guiding the PCs to the subcellular destinations on the secretory pathways: SKI-1/S1P to the cis-Golgi, furin, PC5B, and PC7 to the TGN region but also to the plasma membrane. PACE4, PC5A, and PCSK9 are attached at the cell surface. Truncated, soluble furin and SKI-1/S1P, as well as PC1 and PC2, are released into the extracellular matrix. Many enveloped viruses are activated by furin and furin-like PCs and arenaviruses and a few bunyaviruses by SKI-1/S1P. The PCs cleave the viral fusion glycoprotein to trigger fusion of viral envelopes with cellular membranes to deliver the viral genome into host cells. Cleavage by PCs, occasionally in concert with other endoproteases, enables conformational changes in the viral membrane proteins needed for correct oligomerization of glycoprotein spikes and their effective incorporation into virions. Mutational alterations of PC cleavage sites can reduce the fusion potential of viral surface proteins and thus facilitate the development of secure live attenuated vaccines. Alternatively, agents preventing cleavage of viral surface (glyco)proteins block fusion capacity and multicyclic virus replications. PC inhibitors are suggested as promising antiviral drugs for quite a number of viruses causing severe infections.

Dataset Information

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

Publications

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

Similar Datasets

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