Surette M E, Fonteh A N, Bernatchez C, Chilton F H
Université Laval and Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Ste-Foy, Canada.
Carcinogenesis. 1999 May;20(5):757-63. doi: 10.1093/carcin/20.5.757.
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.
我们之前的研究表明，花生四烯酸 - 磷脂重塑的抑制剂[即非辅酶A依赖性转酰基酶（CoA-IT）]可降低肿瘤细胞的增殖并诱导其凋亡。本研究的目的是阐明与花生四烯酸 - 磷脂重塑相关的影响细胞增殖和存活的分子事件。初步实验通过证明耗尽花生四烯酸的HL-60细胞对CoA-IT抑制诱导的凋亡更具抗性，揭示了细胞花生四烯酸对信号传导过程的重要性。在用CoA-IT抑制剂处理的细胞中，游离花生四烯酸和含花生四烯酸的甘油三酯显著增加。甘油三酯的富集可能是由于花生四烯酸通过从头合成甘油脂质生物合成酰化生成甘油二酯和甘油三酯。为了确定游离脂肪酸影响细胞增殖的潜力，将HL-60细胞与不同浓度的游离脂肪酸一起孵育；外源提供的20碳多不饱和脂肪酸导致细胞增殖的剂量依赖性抑制，而油酸则没有作用。阻断5-脂氧合酶或环氧化酶对花生四烯酸或CoA-IT抑制剂诱导的细胞增殖抑制没有影响。在暴露于游离花生四烯酸或CoA-IT抑制剂的细胞中，检测到细胞相关神经酰胺（主要在16:0 - 神经酰胺部分）增加。这项研究与其他近期研究一起表明，细胞花生四烯酸水平控制的扰动会影响细胞增殖和存活。
