Arachidonate has protumor-promoting action that is inhibited by linoleate in mouse skin carcinogenesis.
Previous studies demonstrated a requirement for arachidonic acid metabolites in tumor development in mouse skin. The goal of this study was to determine whether the arachidonate content of epidermal phospholipids could be altered by increasing dietary levels of linoleate and whether specific metabolites of linoleate and arachidonate have dissimilar biological effects. In a series of tumor studies in which the quantity of dietary linoleate was incrementally increased, a slight reduction in phospholipid levels of arachidonate was observed that correlated with an increased phospholipid level of linoleate and a suppression in tumor yield. A comparison of the arachidonate lipoxygenase metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) with the 13-hydroxyoctadecadienoic acid (13-HODE) lipoxygenase metabolite of linoleate revealed that 12-HETE has biological activities that mimic the phorbol ester tumor promoters, whereas 13-HODE has antithetical effects. Specifically, 12(S)-HETE enhanced the activation of protein kinase C by phorbol esters, mimicked phorbol ester-induced adhesion of keratinocytes to fibronectin and mimicked phorbol ester repression of expression of a differentiation-related gene, keratin-1. 13-HODE blocked 12-HETE-induced cell adhesion and prevented 12-HETE-induced suppression of keratin-1 expression. Overall, these studies suggest that arachidonate and linoleate have opposing functions in the epidermis, particularly with regard to events involved in tumor development.
Fischer
S M
SM
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78759, USA.
Hagerman
R A
RA
Li-Stiles
E
E
Lo
H H
HH
Maldve
R E
RE
Belury
M A
MA
Locniskar
M F
MF
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000818:Animals; D016718:Arachidonic Acid / Q000633:toxicity*; D005260:Female; D006893:Hydroxyeicosatetraenoic Acids / Q000633:toxicity; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology*; D051379:Mice; D010741:Phospholipases A / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000517:prevention & control
D006893:Hydroxyeicosatetraenoic Acids; D008041:Linoleic Acids; D016718:Arachidonic Acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D019787:Linoleic Acid; D011493:Protein Kinase C; D010741:Phospholipases A