uPA, uPAR, PAI-I: Key intersection of proteolytic, adhesive and chemotacfic highways?

doi:10.1016/S0167-5699(97)01121-3

Immunology Today

Volume 18, Issue 9, September 1997, Pages 415-417

Immunology Today

https://doi.org/10.1016/S0167-5699(97)01121-3 Get rights and content

Abstract

Through multiple interactions, the unpkinase plasminogen in tivator (uPA) system forms n self-regulated, surface-located, functionally important chemokine. This article examines new data in the field.

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Oral squamous cell carcinoma (OSCC) counts for 90% of pathology in oral cavity cancer. Oral leukoplakia is the most frequent type of pre-invasive lesion leading to OSCC. An integrated bioinformatics analysis was performed to determine key genes and pathways deregulated in the malignant transformation of leukoplakia to primary OSCC.
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A total of 901 DEGs in primary OSCC compared to leukoplakia were identified. Also, 113 hub genes were determined in the PPI network. Twenty-two hubs were linked with the prognosis of HNSCC patients. The combination of seven genes including PLAU, FADD, SERPINE1, FOSL1, PLAUR, FST, and THBS1 illustrated the most considerable prognostic impact in HNSCC. IRF1 and MAP2K6 were the main TF and protein kinase involved in the malignant transformation of oral leukoplakia to primary OSCC. The most significant pathways and biological processes deregulated in primary OSCC were associated with the immune system. IHC study confirmed the upregulation of PLAU, SERPINE1, and SPP1 in primary OSCC.
The present results unraveled more details underlying the mechanisms involved in the malignant transformation of oral leukoplakia and may help the prognosis of patients with primary OSCC.
Stimuli responsive and receptor targeted iron oxide based nanoplatforms for multimodal therapy and imaging of cancer: Conjugation chemistry and alternative therapeutic strategies
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Cancer being one of the most precarious and second most fatal diseases evokes opportunities for multimodal delivery platforms which will act synergistically for efficient cancer treatment. Multifunctional iron oxide magnetic nanoparticles (IONPs) are being studied for few decades and still attracting increasing attention for several biomedical applications owing to their multifunctional design and intrinsic magnetic properties that provide a multimodal theranostic platform for cancer therapy, monitoring and diagnosis. The review article aims to provide brief information on various surface chemistries involved in modulating IONPs properties to exhibit potential therapy in cancer treatment. The review addresses structural, magnetic, thermal and optical properties of IONPs which aids in the fabrication of efficient multimodal nanoplatform in cancer therapy. The review discussed the pharmacokinetics of IONPs and attributes influencing them. This review inculcates recent advancements in therapies, focused on tumor-microenvironment-responsive and targeted therapy along with their eminent role in cancer diagnosis. The concept of stimuli-responsive including endogenous, exogenous and dual/multi stimuli-based delivery platform demonstrated significantly enhanced anticancer therapy. Several therapeutic approaches viz. chemotherapy, radiotherapy, immunotherapy, hyperthermia, gene therapy, sonodynamic therapy, photothermal, photodynamic-based therapy along with biosensing and several toxicity aspects of IONPs have been addressed in this review for effective cancer treatment.
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Proteases are required in a cell for carrying out various biological processes. The coordination between proteases and their inhibitors maintains the integrity of the cell, whereas any perturbation in coordination leads to diseases like cancer. More recently, it was reported that the serine proteases such as hepsin, maspin, kallikreins, and matriptase-2 are overexpressed in ovarian cancer (OC) and they may contribute to tumor progression by promoting the extracellular lytic activity of tumor cells. This suggests that serine proteases may serve as an important target for the development of anticancer drug. Researchers have highlighted the application of PIs that can reduce the invasiveness and metastatic capabilities of tumor cells by inhibiting extracellular matrix proteolysis or inhibition of a proteolytic cascade. Therefore, the need for an hour is a comprehensive study of proteases and their PIs in order to make specific cancer drugs for clinical use. In this chapter, we have provided an insight into the role of the serine protease and protease inhibitors in OC.
Stimulus-responsive nanoscale delivery systems triggered by the enzymes in the tumor microenvironment
2019, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
When recognized by its receptors on the cell surface, uPA will hydrolyze and activate serine protease plasminogen into plasmin. It is also found that uPA is able to participate in angiogenesis and tissue reconstruction during tumor invasion and metastasis [74], thus, uPA is often considered as an attractive drug target, and developing its inhibitors also brings a promising opportunity for antitumor therapy. P.K. Chakravarty et al. [36] combined the plasmin sensitive sequence, Val-Leu-Lys, with DOX to prepare the first plasminogen prodrug.
The tumor microenvironment is the cellular environment that is also described as the “soil” for supporting tumor growth, proliferation, invasion and metastasis, as well as protecting tumor cells from immunological recognition. Notably, tumor cells can grow much faster than other normal organs and invade surrounding tissues more easily, which results in abnormal expression of enzymes in the tumor microenvironment, including matrix metalloproteinases, cathepsins, phospholipases, oxidoreductases, etc. In opposite, due to the high selectivity and catalytic activity, these enzymes can promote nanoparticles to recognize tumor tissues more accurately, and the more accumulation of drugs at primal tumor sites will enhance therapeutic efficacy with lower systemic toxicity. Therefore, one promising antitumor strategy is to design stimulus-responsive nanoscale delivery systems triggered by the enzymes with the support of various nanocarriers, such as liposomes, micelles and inorganic nanoparticles, etc. In this review, numerous facts were cited to summarize and discuss the typical types of enzyme-stimulus responsive nanoscale delivery systems. More importantly, we also focused on their recent advancements in antitumor therapy, and offered the direction for further studies.
Urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type 1-triggered cell migration
2018, European Journal of Medicinal Chemistry
Citation Excerpt :
However, the currently available therapies are often not efficient enough or may even induce undesired effects [49]. uPAR plays an important role in the regulation of leukocyte trafficking [11]. In particular, we have shown that the capability of uPAR to trigger cell migration depends on its Ser88-Arg-Ser-Arg-Tyr92 chemotactic sequence even in the form of a synthetic, linear peptide (SRSRY) [15–24].
The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration. We and others have previously documented that the uPAR(84–95) sequence, interacts with the formyl peptide receptors (FPR)s, henceforth inducing cell migration of several cell lines, including leukocytes, and the synthetic shorter peptide (Ser⁸⁸-Arg-Ser-Arg-Tyr⁹², SRSRY) retains chemotactic activity in vitro and in vivo. Recently, we have developed the head-to-tail cyclic analog [SRSRY], a new potent and stable inhibitor of monocyte trafficking. This prompted us to develop novel cyclic and linear analogs of [SRSRY] with the aim to broaden the knowledge about structure-activity relationships of peptide [SRSRY]. Herein we report their synthesis, effects on cell migration, conformational and docking analyses which served to envisage a new pharmacophore model for inhibitors of FPR1-triggered cell migration.
Urokinase-controlled tumor penetrating peptide
2016, Journal of Controlled Release
Citation Excerpt :
uPA and its receptor are key components of a cell surface proteolytic cascade used by both tumor cells and activated capillary endothelial cells for basement membrane invasion, a process required for metastasis and angiogenesis. In response to angiogenic agents, endothelial cells in tumor neovessels secrete uPA and upregulate cell surface expression of uPAR [6–8]. uPA has been used for protease-activated systemic drug targeting, and its use is further supported by successful application of uPA-mediated activation of anthrax toxin [9,10], cytotoxic proteins [11], and cytotoxic drug conjugates [12] for tumor therapy.
Tumor penetrating peptides contain a cryptic (R/K)XX(R/K) CendR element that must be C-terminally exposed to trigger neuropilin-1 (NRP-1) binding, cellular internalization and malignant tissue penetration. The specific proteases that are involved in processing of tumor penetrating peptides identified using phage display are not known. Here we design de novo a tumor-penetrating peptide based on consensus cleavage motif of urokinase-type plasminogen activator (uPA). We expressed the peptide, uCendR (RPARSGR ↓ SAGGSVA, ↓ shows cleavage site), on phage or coated it onto silver nanoparticles and showed that it is cleaved by uPA, and that the cleavage triggers binding to recombinant NRP-1 and to NPR-1-expressing cells. Upon systemic administration to mice bearing uPA-overexpressing breast tumors, FAM-labeled uCendR peptide and uCendR-coated nanoparticles preferentially accumulated in tumor tissue. We also show that uCendR phage internalization into cultured cancer cells and its penetration in explants of murine tumors and clinical tumor explants can be potentiated by combining the uCendR peptide with tumor-homing module, CRGDC.
Our work demonstrates the feasibility of designing tumor-penetrating peptides that are activated by a specific tumor protease. As upregulation of protease expression is one of the hallmarks of cancer, and numerous tumor proteases have substrate specificities compatible with proteolytic unmasking of cryptic CendR motifs, the strategy described here may provide a generic approach for designing proteolytically-actuated peptides for tumor-penetrative payload delivery.

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TrenduPA, uPAR, PAI-I: Key intersection of proteolytic, adhesive and chemotacfic highways?

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

Exp. Cell Res.

J. Clin. lnvest.

Br. J. Haematol.

J. Clin. Invest.

EMBO J.

Clin. Cancer Res.

J. Cell Biol.

J. Cell Biol.

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uPA, uPAR, PAI-I: Key intersection of proteolytic, adhesive and chemotacfic highways?