Exp Mol Med.  2004 Feb;36(1):57-64.

Involvement of MAPK pathway in hypoxia-induced up-regulation of urokinase plasminogen activator receptor in a human prostatic cancer cell line, PC3MLN4

• Lee KH
• Choi EY
• Hyun MS
• Kim JR

Abstract

Clinical studies have shown that tumor hypoxia is associated with invasive growth and metastasis and may be an important prognostic factor adversely influencing survival in patients with tumors. To investigate the mechanisms involved in hypoxia-induced invasive growth and metastasis, hypoxia-mediated urokinase plasmalogen activator receptor (uPAR) expression, cellular invasiveness, and mitogen activated protein kinase (MAPK) activation were measured in a prostate cancer cell line, PC3MLN4. The levels of uPAR expression and cellular invasiveness were increased in hypoxic cells. Hypoxia-induced cellular invasiveness was blocked by an anti-uPAR monoclonal antibody. Phosphorylations of ERK and p38 kinases were also more extensive in hypoxic cells than in normoxic cells. Hypoxia-induced uPAR up-regulation was inhibited by pre-treatments with a specific inhibitor of MEK, PD98059 and a specific inhibitor of p38 MAP kinase, SB203580. Cell growth also increased in hypoxic cells. From these results, hypoxia increased tumor cell invasion by up-regulating uPAR expression, which might be mediated through ERK and p38 kinase signaling pathways in PC3MLN4 prostate cancer cell line.

Keyword

HGF; hypoxia; MAPK; metastasis; uPAR

MeSH Terms

Animals
Anoxia/*metabolism
Cell Line, Tumor
Cell Proliferation
Humans
MAP Kinase Signaling System/*physiology
Male
Mitogen-Activated Protein Kinases/*metabolism
Phosphorylation
Prostatic Neoplasms/*metabolism/pathology
Protein Kinase Inhibitors/metabolism
Receptors, Cell Surface/genetics/*metabolism
Research Support, Non-U.S. Gov't
*Up-Regulation