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

Young Yoon So, Jung Lee Yoo, Hong Seo Jae, Jung Sung Hwa, Hwa Park Kyong, Keun Choi In, Jin Kim Seok, Cheul Oh Sang, Won Choi Chul, Soo Kim Byung, Won Shin Sang, Hong Kim Yeul, Jun Suk Kim

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)75-81
Number of pages7
JournalCell Research
Volume16
Issue number1
DOIs
Publication statusPublished - 2006 Jan 19

Keywords

  • ERK phosphorylation
  • Hypoxia
  • MDA-MB-231
  • iNOS
  • uPAR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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