Submitted on July 17, 2006
Revised on December 8, 2006
Accepted on December 11, 2006
Inducible expression of human 15-lipoxygenase-2 and the orthologous mouse 8-lipoxygenase inhibits cell growth via common signalling pathways
Dorothea Schweiger, Gerhard Fürstenberger, and Peter Krieg
Eisosanoids and Tumor Development, Deutsches Krebsforschungszentrum, Heidelberg D-69120
Corresponding Author: p.krieg{at}dkfz.de
Human 15-lipoxygenase (LOX)-2 and mouse 8-LOX represent orthologous members of the LOX family, but display different positional specificities and tissue distribution. To study the functional role of 15-LOX-2 and 8-LOX in keratinocytes an inducible tet-on gene expression system was established in the premalignant mouse keratinocyte cell line 308. Doxycycline (dox)-induced expression of enzymatically active 15-LOX-2 and 8-LOX led to an inhibition of cell growth that was associated with inhibition of DNA synthesis as shown by a 15% to 46% reduction of BrdU incorporation. The inhibitory effects were increased in the presence of exogenous arachidonic acid. In contrast, addition of linoleic acid or the LOX inhibitor baicalein reversed the growth-inhibitory effects. Treatment of the cells with 15-HETE or 8-HETE resulted in a similar inhibition of BrdU incorporation while 13-HODE and 9-HODE, in contrast, had no effects. Dox-induced keratinocytes showed elevated levels of reactive oxygen species (ROS). The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 MAP kinase, but not of ERK1/2 or JNK/SAP kinases, completely abolished the LOX-induced growth inhibition indicating a critical role of ROS and p38. Our data suggest that 15-LOX-2 and 8-LOX although displaying different positional specificity may utilize common signalling pathways to induce growth inhibition in premalignant epithelial cells.
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