Deregulation of the signaling pathways controlling urokinase production

Abstract

We review the evidence in support of the notion that, upon experimental oncogenic transformation or in spontaneous human cancers, mitogenesis and expression of urokinase (uPA) and its receptor (uPAR) are activated through common signaling complexes and pathways. It is well documented that uPA, uPAR or metalloproteinases (MMPs) are overexpressed in tumor cells of mesenchymal or epithelial origin and these molecules are required for tumor invasion and metastasis. Furthermore, oncogenic stimuli, which may render the transformed cells tumorigenic and metastatic in vivo, activate, in a constitutive fashion, the extracellular-regulated kinases (Erk 1 and 2) classical mitogenic pathway and others such as the NH(2)-Jun-kinase (Jnk). Cells from human tumors or oncogene-transformed cells overexpress uPA and uPAR, and also show a sustained activation of the above-mentioned signaling modules. In this paper we show that the classical mitogenic pathway involving Ras-Erk, PKC-Erk or Rac-JNK, among others, is activated by growth factors or endogenously by oncogenes, and constitutively activates uPA and uPAR expression. All the data obtained from human tumors or experimental systems, incorporated into a general model, indicate that oncogenic stimuli lead to the constitutive activation of mitogenesis and uPA and its receptor expression, through the activation of the same classical and nonclassical signaling complexes and pathways that regulate cell proliferation. We also discuss contrasting points of view. For instance, what governs the differential regulation of mitogenesis and the signal that leads to protease overexpression in a way that allows normal cells during physiological events to respond to growth factors, and proliferate without overexpressing extracellular matrix (ECM) proteases? Or how can cells remodel their microenvironment without proliferating? What restrains benign tumors from overexpressing tumor-associated proteases when they certainly have the mitogenic signal fully activated? This may occur by the differential regulation of transcriptional programs and recent reports reviewed in this paper may provide an insight into how this occurs at the signaling and transcriptional levels.

Regulation of hepatocyte growth factor-mediated urokinase plasminogen activator secretion by MEK/ERK activation in human stomach cancer cell lines

“…In addition, binding of uPA to its receptor can stimulate epithelial cell motility by a mechanism that is independent of proteolysis (Juan et al, 2001). uPA expression can be regulated by growth factors that bind to tyrosine kinase receptors and this activates the Ras signaling pathway (Aguirre-Guiso et al, 1999). This pathway involves the activation of MAPK by c-Raf, which in turn activates the extracellular signal regulated kinase (ERK).…”

Inhibitory Effect of Selenite on Invasion of HT1080 Tumor Cells

“…The role of MAPKs in regulation of MMP-9 and uPA expressions in malignant cells has been well understood. At least two (extracellular signalregulated kinase and c-Jun NH 2 -terminal kinase/stress-activated protein kinase) of the three so-called mitogenic pathways known so far in mammalian cells induce up-regulation of MMP-9 and uPA (41,42). Recently it has been shown that inhibition of p38 leads to reduced MMP-9 expression and invasion by tumor cells (43), and p38 stabilizes uPA mRNA and invasiveness in MDA-MB-231 cells (44).…”

Negative regulation of urokinase-type plasminogen activator production through FGF-2-mediated activation of phosphoinositide 3-kinase

“…This step is involved in both tumor invasion and the initial step of angiogenesis (see reviews; Aguirre-Ghiso et al, 1999a;Blasi, 1993). This protease itself has serine protease activity and also acts as an upstream regulator of plasmin and matrix metalloproteases (MMPs).…”