Abstract
The urokinase receptor (uPAR) is a GPI-anchored membrane protein, which regulates protease activity at the cell surface and, in collaboration with a system of co-receptors, triggers cell-signaling and regulates gene expression within the cell. In normal tissues, uPAR gene expression is limited; however, in cancer, uPAR is frequently over-expressed and the gene may be amplified. Hypoxia, which often develops in tumors, further increases uPAR expression by cancer cells. uPAR-initiated cell-signaling promotes cancer cell migration, invasion, metastasis, epithelial-mesenchymal transition, stem cell-like properties, survival, and release from states of dormancy. Newly emerging data suggest that the pro-survival cell-signaling activity of uPAR may allow cancer cells to “escape” from the cytotoxic effects of targeted anticancer drugs. Herein, we review the molecular properties of uPAR that are responsible for its activity in cancer cells and its ability to counteract the activity of anticancer drugs.
Highlights
Urokinase receptor and resistance to targeted anticancer agentsSpecialty section: This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology
Adhesion receptors that mediate interactions between adjacent cells or with extracellular matrix (ECM) and at the same time, initiate cell-signaling include the integrins and members of the cadherin superfamily (Giancotti and Ruoslahti, 1999; Angst et al, 2001)
These results suggest that the urokinase-type plasminogen activator (uPA)-urokinase receptor (uPAR) signaling system may provide a major escape pathway for GBM cells when tumors are treated with EGF receptor (EGFR)-targeting therapeutics
Summary
Specialty section: This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology. The urokinase receptor (uPAR) is a GPI-anchored membrane protein, which regulates protease activity at the cell surface and, in collaboration with a system of co-receptors, triggers cell-signaling and regulates gene expression within the cell. Hypoxia, which often develops in tumors, further increases uPAR expression by cancer cells. UPAR-initiated cell-signaling promotes cancer cell migration, invasion, metastasis, epithelial-mesenchymal transition, stem cell-like properties, survival, and release from states of dormancy. Emerging data suggest that the pro-survival cell-signaling activity of uPAR may allow cancer cells to “escape” from the cytotoxic effects of targeted anticancer drugs. We review the molecular properties of uPAR that are responsible for its activity in cancer cells and its ability to counteract the activity of anticancer drugs
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