uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line

Abstract

Urokinase plasminogen activator receptor (uPAR) plays a major role in cancer invasion and metastasis and uPAR expression is correlated with a poor prognosis in various cancer types. Moreover, the expression of uPAR is increased under hypoxic conditions. Nitric oxide (NO) and its metabolites produced by inducible nitric oxide synthase (iNOS) are important products of hypoxic stress, and NO may activate or modulate extracellular signal regulated kinase (ERK). Here, we evaluated uPA, uPAR, and activated ERK levels under hypoxic conditions, and the modulatory effects of iNOS and NO in the MDA-MB-231 human breast cancer cell line. Cells were incubated in a hypoxic or normoxic incubator and treated with PD98059 (a MEK 1/2 inhibitor, which abrogates ERK phosphorylation) and aminoguanidine (a selective iNOS inhibitor). uPAR expression, ERK phosphorylation, and uPA activity were found to be increased under hypoxic conditions. Moreover, when cells were treated with PD98059 under hypoxic conditions, uPAR was downregulated, whereas aminoguanidine markedly increased ERK phosphorylation in a dose dependent manner. Furthermore, aminoguanidine increased uPAR expression and prevented the inhibition of uPAR expression by PD98059. These results demonstrated that uPAR is induced by hypoxia and that increased uPAR expression is mediated by ERK phosphorylation, which in turn is modulated by iNOS/NO in MDA-MB-231 cells. We conclude that iNOS/NO downregulates the expression of uPAR under hypoxic conditions via ERK pathway modulation.

Long-term interferon-α treatment suppresses tumor growth but promotes metastasis capacity in hepatocellular carcinoma

“…The present study showed that increased tumor hypoxia associated with up-regulation of metastasisrelated genes such as uPA, c-met, PDGF-A, and IL-8 as well as relatively more CTCs. It has been reported that c-met, uPA, and IL-8 expression regulated by hypoxia facilitated movement of tumor cells into the circulation, thus increasing the number of CTCs (Pennacchietti et al 2003;Mizukami et al 2005;Yoon et al 2006). The increased expression of hypoxia-related invasive factors induced by IFN-could render the tumor to be more invasive by escaping the primary site.…”

Nuclear Translocation of Hand-1 Acts as a Molecular Switch to Regulate Vascular Radiosensitivity in Medulloblastoma Tumors: The Protein uPAR Is a Cytoplasmic Sequestration Factor for Hand-1

“…The literature has shown that HIF-1A activation promotes transcriptional activation of uPAR in cancer cells (48,70,71), thereby indicating that a mutual regulatory mechanism exists between HIF-1A and uPAR signaling mechanisms, which regulates the angiogenesis tube-inducing ability and adaptation to radiation treatment of both cancer cells and CSCs (Fig. 5F).…”

Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages

“…The mitogen-activated protein kinases kinase (MEK)/extracellular signal-regulated kinases (ERKs) signaling cascade plays an important role in the differentiation of MSCs (Joannides et al 2003;Jaiswal et al 2000). Treatment of adult human MSCs with osteogenic conditioned medium results in sustained ERK activation, whereas the inhibition of ERK activation blocks osteogenic differentiation in a dose-dependent manner, as does transfection with a dominant negative form of MEK, an upstream kinase regulating ERK (Jaiswal et al 2000;Yoon et al 2006;Yang et al 2006;Guerriero et al 2006). Moreover, activation of ERK contributes to the induction of cell migration and epithelial-mesenchymal transition (Irie et al 2005).…”