REGULATION OF CELL GROWTH BY LINOLEIC ACID METABOLITES IN SHE CELLS

工作总结：我们利用叙利亚仓鼠胚胎细胞(SHE)进行了研究 脂代谢产物对细胞生长和凋亡的调节作用。EGF- 依赖的有丝分裂被脂氧合酶抑制剂抑制，但不是 被PGHS抑制剂减弱。EGF对前列腺素无刺激作用 形成，但确实刺激亚油酸的代谢到13(S)- 霍德。13-HODE的形成受酪氨酸激酶的调节 EGF受体的活性，但其机制尚不清楚。这个 亚油酸代谢产物增强EGF依赖的细胞有丝分裂 SupB+SHE细胞，但这种反应在进展到supB-的过程中丢失。 构效关系研究表明，13(S)-HpODE含量最高 有效脂类化合物刺激EGF调节的DNA合成 她的细胞。这提示了13(S)-HpODE效应的特定部位。自.以来 13(S)-HODE的形成上调表皮生长因子依赖的细胞生长 制备过表达15-蛋白的稳定的SuB+细胞 脂氧合酶。这增加了15-脂氧合酶的表达和 13(S)-HpODE的形成使细胞生长速度提高4倍。这些 研究结果为脂类代谢物作为调节剂提供了更多证据 细胞增殖率。

Summary of Work: We have used Syrian hamster embryo cells (SHE) to study the modulation of cell growth and apoptosis by lipid metabolites. EGF- dependent mitogenesis was inhibited by lipoxygenase inhibitors but not attenuated by PGHS inhibitors. EGF did not stimulate prostaglandin formation but did stimulate the metabolism of linoleic acid to 13(S)- HODE. The formation of 13-HODE is regulated by the tyrosine kinase activity of the EGF receptor but the mechanism is poorly understood. The linoleic acid metabolite potentiated EGF-dependent mitogenesis in the supB+ SHE cells but this response was lost on progression to the supB-. Structure-activity investigations revealed that 13(S)-HpODE was the most effective lipid compound in stimulating EGF-regulated DNA synthesis in SHE cells. This suggested a specific site for 13(S)-HpODE effects. Since the formation of 13(S)-HODE up-regulates EGF-dependent cell growth, we prepared stable transfectants of supB+ cells that over-express 15- lipoxygenase. This increased expression of 15-lipoxygenase and the formation of 13(S)-HpODE increases the rate of cell growth 4 fold. These findings provide additional evidence for lipid metabolites as regulators of cell proliferation.