Volume 16, No 1, Jan 2006

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 16 Issue 1, January 2006: 75-81

ORIGINAL ARTICLES

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

So Young Yoon¹, Yoo Jung Lee², Jae Hong Seo³, Hwa Jung Sung³, Kyong Hwa Park³, In Keun Choi³, Seok Jin Kim³, Sang Cheul Oh³, Chul Won Choi³, Byung Soo Kim³, Sang Won Shin³, Yeul Hong Kim³, Jun Suk Kim³

¹Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, Konkuk University, Seoul 143-729, Korea; ²Graduate School of Medicine, Korea University, Seoul 136-701, Korea; ³Division of Oncology, Department of Internal Medicine, College of Medicine, Korea University, Seoul 425-707, Korea Correspondence: Jae Hong Seo,(cancer@korea.ac.kr)

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 andNO in the MDA-MB-231 human breast cancer cell line. Cells were incubated in a hypoxic or normoxic incubator andtreated 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.

Cell Research (2006) 16:75-81. doi:10.1038/sj.cr.7310010; published online 16 January 2006

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