Abstract
Proteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; it includes the serine-protease urokinase-type plasminogen activator (uPA). uPA binds to a specific cellular receptor (uPAR), which concentrates proteolytic activity at the cell surface, thus supporting cell migration. However, a large body of evidence clearly showed uPAR involvement in the biology of cancer cell independently of the proteolytic activity of its ligand. In this review we will first describe this multifunctional molecule and then we will discuss how uPAR can sustain most of cancer hallmarks, which represent the biological capabilities acquired during the multistep cancer development. Finally, we will illustrate the main data available in the literature on uPAR as a cancer biomarker and a molecular target in anti-cancer therapy.
Highlights
Proteolysis is a fundamental event in several biological processes; at present, more than 550 human proteases are known, representing the second most abundant class of enzymes after ubiquitin ligases [1]
UPA increases uPA binds to a specific cellular receptor (uPAR) binding to VN, possibly by controlling uPAR oligomerization and localization in lipid rafts [25]; biochemical analyses have shown a 1/1/1 stoichiometry of urokinase-type plasminogen activator (uPA)/uPAR/somatomedin B domain (SMB) complexes, suggesting the need of alternative mechanisms, such as a uPA-driven allosteric regulation of uPAR [10]. These findings indicate that uPAR can form a ternary complex with uPA and VN, coordinating cell adhesion and pericellular proteolysis
We demonstrated that uPAR is able to recruit a large fraction of both FPR1 and beta1 integrins at the cell surface of HEK-293 cells, strongly promoting their colocalization when cells were stimulated with serum
Summary
Proteolysis is a fundamental event in several biological processes; at present, more than 550 human proteases are known, representing the second most abundant class of enzymes after ubiquitin ligases [1]. UPAR silencing in human vascular smooth muscle cells (VSMCs) results in abrogation of doxorubicininduced cellular senescence, whereas uPAR overexpression promotes VSMC senescence, regulating the proteasomal degradation of telomeric repeat binding factor 2 (TRF2), which plays a key role in the protective activity of telomeres [85] and activates the DNA singlestrand break repair signaling pathway [86]. UPAR -/- mouse embryonic fibroblasts (MEFs) grow faster than wt MEFs and infection with a uPAR-containing retrovirus decreases their growth rate; proliferation of wt MEFs appears do not involve FPRs or integrins [93], which instead may contribute to the proliferative advantage observed in the other reports [91,92], suggesting different regulatory mechanisms in MEFs. uPA promotes uPAR association with the PDGFR, leading to downstream signaling regulating proliferation of vascular smooth muscle cells [94]. In uPAR KO cells, authors observe an increased number of mitochondria in two melanoma cell lines and an immature biogenesis of mitochondria in the colon carcinoma line, accompanied by a significant enhancement of the mitochondrial respiratory capacity and a decreased glycolysis, even though with an increased secretion of lactate [103]
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