Dwa. Beno et al., LIPOXYGENASE INHIBITORS BLOCK PDGF-INDUCED MITOGENESIS - A MAPK-INDEPENDENT MECHANISM THAT BLOCKS FOS AND EGR, American journal of physiology. Cell physiology, 37(3), 1995, pp. 604-610
Hepatic Ito cells proliferate during liver injury and fibrogenesis. Pl
atelet-derived growth factor (PDGF)-induced [H-3]thymidine incorporati
on was studied as Ito cells express the PDGF receptor after injury and
activation. Pretreatment with either the nonspecific lipoxygenase inh
ibitor (nordihydroguaiaretic acid) or specific inhibitors of 5-Lipoxyg
enase (SC-41661 and ICI-230487) inhibited PDGF-induced mitogenesis. It
o cells predominantly produce the leukotriene (LT) C-4 much greater th
an LTB(4). The PDGF-induced signal transduction cascade was studied to
determine the potential mechanism of action of the Lipoxygenase inhib
itors. It was found that PDGF receptor abundance and receptor activati
on were not altered by lipoxygenase inhibition, suggesting that a post
receptor mechanism was involved. The two-key cytoplasmic serine-threon
ine 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 signal
ing, this suggests that the mechanism of action lies parallel or dista
l 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 suppress
ion of mitogenesis in part by disrupting the nuclear signaling that is
required for protooncogene transcription at a step distal or parallel
to MAPK activation.