Borek C, Ong A, Stevens V L, Wang E, Merrill A H
Department of Radiation Oncology, Tufts University School of Medicine, New England Medical Center, Boston, MA 02111.
Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1953-7. doi: 10.1073/pnas.88.5.1953.
Sphingosine and other long-chain (sphingoid) bases inhibit protein kinase C, the putative cellular receptor for the tumor promoter phorbol 12-myristate 13-acetate (PMA), and exert potent effects on diverse cell functions. We tested the ability of long-chain bases to modulate multistage carcinogenesis in mouse C3H/10T1/2 cells exposed to gamma-rays and PMA. Sphingosine and sphinganine completely blocked the enhancement of radiation-induced transformation by PMA (promotion) and partially suppressed transformation by radiation alone. N-Acetylsphingosine, a ceramide analog, did not inhibit transformation. Sphingosine was rapidly taken up by the cells and metabolized; hence, the long-chain bases were added daily to achieve prolonged inhibition. Long-chain bases inhibited protein kinase C activity in C3H/10T1/2 cells and suppressed the down-regulation of this enzyme by PMA. Our results establish that long-chain bases are highly effective inhibitors of carcinogenesis in this model. Our results also indicate that the suppressive effects may be mediated, in part, by inhibition of protein kinase C. The data suggest that sphingosine and other long-chain bases derived from complex sphingolipids may act as cancer-preventative agents.
鞘氨醇和其他长链（鞘氨醇类）碱基可抑制蛋白激酶C，而蛋白激酶C被认为是肿瘤促进剂佛波酯12 - 肉豆蔻酸酯13 - 乙酸酯（PMA）的细胞受体，并且对多种细胞功能具有显著影响。我们测试了长链碱基对暴露于γ射线和PMA的小鼠C3H/10T1/2细胞多阶段致癌作用的调节能力。鞘氨醇和二氢鞘氨醇完全阻断了PMA对辐射诱导转化的增强作用（促进作用），并部分抑制了仅由辐射引起的转化。神经酰胺类似物N - 乙酰鞘氨醇不抑制转化。鞘氨醇被细胞迅速摄取并代谢；因此，每天添加长链碱基以实现长期抑制。长链碱基抑制C3H/10T1/2细胞中的蛋白激酶C活性，并抑制PMA对该酶的下调作用。我们的结果表明，在该模型中长链碱基是非常有效的致癌作用抑制剂。我们的结果还表明，抑制作用可能部分是由蛋白激酶C的抑制介导的。数据表明，鞘氨醇和其他源自复杂鞘脂的长链碱基可能作为癌症预防剂。
