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Journal of Lipid Research, Vol. 48, 553-564, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways

Dorothea Schweiger, Gerhard Fürstenberger and Peter Krieg¹

Division of Eicosanoids and Tumor Development, German Cancer Research Center, D-69120 Heidelberg, Germany

Published, JLR Papers in Press, December 11, 2006.

¹ To whom correspondence should be addressed. e-mail: 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 an inhibition of DNA synthesis, as shown by a 15–46% reduction of 5-bromo-2-deoxy-uridine (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-hydroxyeicosatetraenoic acid (HETE) or 8-HETE resulted in a similar inhibition of BrdU incorporation, whereas 13-hydroxyoctadecadienoic acid (HODE) and 9-HODE, in contrast, had no effects. Dox-induced keratinocytes showed increased levels of reactive oxygen species (ROS). The antioxidant N-acetyl-L-cysteine and a specific inhibitor of p38 mitogen-activated protein kinase, but not of extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase/stress-activated 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 use common signaling pathways to induce growth inhibition in premalignant epithelial cells.

Supplementary key words keratinocyte • reactive oxygen species • antioxidant • mitogen-activated protein kinases

Abbreviations: AA, arachidonic acid; dox, doxycycline; BrdU, 5-bromo-2-deoxy-uridine; DCF, 2',7'-dichlorofluorescein diacetate; ERK, extracellular signal-regulated kinase; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; HPETE, hydroperoxyeicosatetraenoic acid; HPODE, hydroperoxyoctadecadienoic acid; JNK, c-Jun N-terminal kinase; LA, linoleic acid; LOX, lipoxygenase; MAPK, mitogen-activated protein kinase; NAC, N-acetyl-L-cysteine; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species

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