Carcinogenesis, Vol. 20, No. 5, 757-763,
May 1999
© 1999 Oxford University Press
Perturbations in the control of cellular arachidonic acid levels block cell growth and induce apoptosis in HL-60 cells
1 Université Laval and Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Laurier, Ste-Foy, Québec G1V 4G2, Canada,
2 Section on Pulmonary and Critical Care Medicine and
3 Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157–1054, USA
Our previous studies demonstrated that inhibitors of arachidonate–phospholipid remodeling [i.e. the enzyme CoA-independent transacylase (CoA-IT)] decrease cell proliferation and induce apoptosis in neoplastic cells. The goal of the current study was to elucidate the molecular events associated with arachidonate–phospholipid remodeling that influence cell proliferation and survival. Initial experiments revealed the essential nature of cellular arachidonate to the signaling process by demonstrating that HL-60 cells depleted of arachidonate were more resistant to apoptosis induced by CoA-IT inhibition. In cells treated with CoA-IT inhibitors a marked increase in free arachidonic acid and AA-containing triglycerides were measured. TG enrichment was likely due to acylation of arachidonic acid into diglycerides and triglycerides via de novo glycerolipid biosynthesis. To determine the potential of free fatty acids to affect cell proliferation, HL-60 cells were incubated with varying concentrations of free fatty acids; exogenously provided 20-carbon polyunsaturated fatty acids caused a dose-dependent inhibition of cell proliferation, whereas oleic acid was without effect. Blocking 5-lipoxygenase or cyclooxygenases had no effect on the inhibition of cell proliferation induced by arachidonic acid or CoA-IT inhibitors. An increase in cell-associated ceramides (mainly in the 16:0-ceramide fraction) was measured in cells exposed to free arachidonic acid or to CoA-IT inhibitors. This study, in conjunction with other recent studies, suggests that perturbations in the control of cellular arachidonic acid levels affect cell proliferation and survival.
Abbreviations: AA, arachidonic acid; CoA-IT, CoA-independent transacylase; DG, diacylglycerol; ESI-MS/MS, electrospray ionization-tandem mass spectrometry; EtBr, ethidium bromide; FBS, fetal bovine serum; FSC, forward scatter; 2H3-SA, trideuterated stearic acid; 2H8-AA, octadeuterated AA; HAS, human serum albumin; HBSS, Hank's balanced salt solution; MG, monoacylglycerol; NICI-GC/MS, negative ion chemical ionization gas chromatography/mass spectrometry; TCA, trichloroacetic acid; TG, triacylglycerol; TLC, thin-layer chromatography.
4 To whom correspondence should be addressed Email: marc.surette{at}crchul.ulaval.ca
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