Lipoxygenase inhibitors block PDGF-induced mitogenesis: a MAPK-independent mechanism that blocks fos and egr.

Hepatic Ito cells proliferate during liver injury and fibrogenesis. Platelet-derived growth factor (PDGF)-induced [3H]thymidine incorporation was studied as Ito cells express the PDGF receptor after injury and activation. Pretreatment with either the nonspecific lipoxygenase inhibitor (nordihydroguaiaretic acid) or specific inhibitors of 5-lipoxygenase (SC-41661 and ICI-230487) inhibited PDGF-induced mitogenesis. Ito cells predominantly produce the leukotriene (LT) C4 >> LTB4. The PDGF-induced signal transduction cascade was studied to determine the potential mechanism of action of the lipoxygenase inhibitors. It was found that PDGF receptor abundance and receptor activation were not altered by lipoxygenase inhibition, suggesting that a postreceptor mechanism was involved. The two-key cytoplasmic serine-threonine kinases Raf and MAPK (mitogen-activated protein kinase), which are induced by PDGF and transmit the signal to the nucleus, were also not altered. Because Raf and MAPK can independently induce nuclear signaling, this suggests that the mechanism of action lies parallel or distal to these secondary messengers. Lipoxygenase inhibition did result in the suppression of PDGF-induced fos and egr expression. Collectively, this work suggests that lipoxygenase inhibition leads to the suppression of mitogenesis in part by disrupting the nuclear signaling that is required for protooncogene transcription at a step distal or parallel to MAPK activation.