Heiligtag S J, Bredehorst R, David K A
Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813, USA.
Cell Death Differ. 2002 Sep;9(9):1017-25. doi: 10.1038/sj.cdd.4401055.
Cerulenin, a fungal metabolite, is known to be a specific inhibitor of fatty acid synthase. Here we report that cerulenin is an effective inducer of apoptosis in different wild-type p53 and mutant p53 tumor cell lines, whereas normal human keratinocytes and fibroblasts are resistant to the apoptotic effect. To get more insight into the mechanisms of how cerulenin induces apoptosis we investigated several signal transduction molecules, including p53, p73, p21/WAF1, Bax, cytochrome c, and caspases 3 and 9. Our data strongly indicate that mitochondria play a key role in the cerulenin-mediated pathway. Bax overexpression correlated with the extent of apoptosis and appears to be regulated in a p53-independent manner. The significance of the mitochondrial pathway for the cerulenin-mediated apoptosis was confirmed by the rapid mitochondrial release of cytochrome c both in wild-type p53 and mutant cell lines. Interestingly, the rapid release of cytochrome c was not accompanied by a breakdown of the mitochondrial potential. Instead, the complete disruption of the mitochondrial function coincided with the appearance of a p18 kDa cleavage product of Bax.
浅蓝菌素是一种真菌代谢产物，已知它是脂肪酸合酶的特异性抑制剂。在此我们报告，浅蓝菌素是不同野生型p53和突变型p53肿瘤细胞系中凋亡的有效诱导剂，而正常人角质形成细胞和成纤维细胞对其凋亡效应具有抗性。为了更深入了解浅蓝菌素诱导凋亡的机制，我们研究了几种信号转导分子，包括p53、p73、p21/WAF1、Bax、细胞色素c以及半胱天冬酶3和9。我们的数据强烈表明线粒体在浅蓝菌素介导的途径中起关键作用。Bax的过表达与凋亡程度相关，并且似乎以p53非依赖的方式受到调控。在野生型p53和突变细胞系中细胞色素c从线粒体的快速释放证实了线粒体途径对浅蓝菌素介导的凋亡的重要性。有趣的是，细胞色素c的快速释放并未伴随着线粒体膜电位的崩溃。相反，线粒体功能的完全破坏与Bax的一种18 kDa裂解产物的出现同时发生。
