12(S)-hydroxyeicosatetraenoic acid regulates DNA synthesis and protooncogene expression induced by epidermal growth factor and insulin in rat lens epithelium.
12(S)-hydroxyeicosatetraenoic acid regulates DNA synthesis and protooncogene expression induced by epidermal growth factor and insulin in rat lens epithelium.
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发表时间：
1994-10
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通讯作者：
T. Lysz;J. Arora;C. Lin;P. Zelenka
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作者：
T. Lysz;J. Arora;C. Lin;P. Zelenka
新生大鼠晶状体上皮具有较高的12(S)-羟基二十碳四烯酸[12(S)-HETE]合成能力，但随着年龄的增长，上皮细胞增殖能力下降，合成能力也会降低。为了确定 12-脂氧合酶途径的产物是否参与晶状体细胞增殖，我们测量了 12-脂氧合酶抑制剂对培养的新生大鼠晶状体上皮细胞中内源 12-HETE 产生、表皮生长因子/胰岛素刺激的 DNA 合成和原癌基因表达的影响。将新生大鼠晶状体在表皮生长因子加胰岛素中孵育，可刺激内源性 12-HETE 产生 8 至 10 倍，并在 2 至 3 小时后产生 c-fos 和 c-myc mRNA 的瞬时诱导，随后大约 20 小时后进行一轮 DNA 合成。脂氧合酶抑制剂肉桂基-3,4-二羟基-α-氰基肉桂酸酯强烈抑制内源性 12-HETE 合成和生长因子刺激的 DNA 合成，半最大抑制在 10 至 20 microM 之间。 3,4-二羟基-α-氰基肉桂酸酯 (10 microM) 还抑制 c-fos 和 c-myc mRNA 的表达，并在较小程度上抑制 c-jun mRNA 的表达。 0.3 microM 12(S)-HETE 可阻止肉桂基-3,4-二羟基-α-氰基肉桂酸酯对原癌基因表达和 DNA 合成的抑制作用，但不会被同等浓度的 5(S)-HETE 或 15(S)-HETE 阻止。这些发现表明，内源合成的 12(S)-HETE 可能通过调节原癌基因的表达来介导新生大鼠晶状体上皮细胞中表皮生长因子/胰岛素刺激的 DNA 合成。
Neonatal rat lens epithelium has a high 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] synthetic capacity, which decreases as epithelial cell proliferation decreases with age. To determine whether products of the 12-lipoxygenase pathway are involved in lens cell proliferation, we measured the effect of 12-lipoxygenase inhibitors on endogenous 12-HETE production, epidermal growth factor/insulin-stimulated DNA synthesis and protooncogene expression in cultured neonatal rat lens epithelial cells. Incubation of neonatal rat lenses in epidermal growth factor plus insulin, which stimulated endogenous 12-HETE production 8- to 10-fold, also produced a transient induction of c-fos and c-myc mRNAs after 2 to 3 h, followed by a round of DNA synthesis approximately 20 h later. The lipoxygenase inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate, strongly inhibited both the endogenous 12-HETE synthesis and growth factor-stimulated DNA synthesis with a half-maximal inhibition between 10 and 20 microM. Cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (10 microM) also inhibited the expression of c-fos and c-myc mRNA and, to a lesser extent, c-jun mRNA. The inhibitory effects of cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate on protooncogene expression and DNA synthesis were prevented by 0.3 microM 12(S)-HETE but not by equivalent concentrations of either 5(S)-HETE or 15(S)-HETE. These findings suggest that endogenously synthesized 12(S)-HETE may mediate epidermal growth factor/insulin-stimulated DNA synthesis in neonatal rat lens epithelial cells by regulating protooncogene expression.