文章：

黑色素瘤细胞如何逃避TRAIL诱导的细胞凋亡

How melanoma cells evade trail-induced apoptosis

原文发布日期：2001-11-01

DOI: 10.1038/35101078

类型: Review Article

开放获取: 否

要点：

1. Several natural defence mechanisms kill melanoma cells by apoptosis. These are induced by granzyme B or interaction with members of the tumour necrosis factor (TNF) family, such as TNF-related apoptosis-inducing ligand (TRAIL).
2. As a consequence, melanoma cells that survive in the host might do so because they have been selected for resistance to apoptosis. Resistance mechanisms include low death-receptor expression and inhibition of intracellular death pathways.
3. Induction of p53 is important in upregulation of TRAIL death receptors in response to DNA damage, but relatively little is known about the control of constitutive expression. Fresh isolates of melanoma cells have low death-receptor expression and development of treatments that increase their expression are crucial for the success of TRAIL-dependent killing of melanoma.
4. One of the main inhibitors of TRAIL-induced apoptosis is the inhibitors of apoptosis (IAP) family, particularly XIAP. XIAP levels are reduced after exposure to TRAIL because TRAIL induces release of a pro-apoptotic protein, SMAC/DIABLO, from mitochondria, which binds to and inactivates members of the IAP family. This represents an alternative to the classical mitochondrial death pathway, which is limited in most melanoma cells by low or absent APAF1 levels.
5. SMAC/DIABLO release from the mitochondria of TRAIL-resistant melanoma cells is decreased, possibly due to stabilization of mitochondrial permeability by the BCL2 family.
6. The transcription factor NF-κB and the mitogen-activated protein kinase (MAPK) and extracellular-regulated kinase (ERK) 1 and 2 pathways seem to be the principal regulators of the IAP and BCL2 family, respectively.
7. These findings provide insights into resistance of melanoma to apoptosis and provide a framework for therapeutic approaches based on providing pro-apoptotic stimuli, as well as reducing anti-apoptotic mechanisms.

要点翻译：

1. 多种天然防御机制通过凋亡途径杀死黑色素瘤细胞。这些机制由颗粒酶B或与肿瘤坏死因子（TNF）家族成员（如TNF相关凋亡诱导配体TRAIL）的相互作用所诱导。
2. 因此，能够在宿主体内存活的黑色素瘤细胞可能是因获得了凋亡抗性而被筛选出来的。其抵抗机制包括死亡受体表达水平低下以及细胞内死亡通路被抑制。
3. p53蛋白的诱导对于响应DNA损伤而上调TRAIL死亡受体至关重要，但关于其组成型表达的调控机制目前知之甚少。新鲜分离的黑色素瘤细胞死亡受体表达水平较低，因此开发能增强其表达的治疗方法对于实现TRAIL依赖性黑色素瘤杀伤至关重要。
4. TRAIL诱导凋亡的主要抑制因子之一是凋亡抑制蛋白（IAP）家族，尤其是X连锁凋亡抑制蛋白（XIAP）。TRAIL暴露后XIAP水平会降低，因为TRAIL能诱导线粒体释放促凋亡蛋白SMAC/DIABLO，该蛋白可与IAP家族成员结合并使其失活。这代表了经典线粒体死亡通路的替代途径——由于大多数黑色素瘤细胞中APAF1蛋白水平低下或缺失，经典通路的作用有限。
5. 在TRAIL抗性黑色素瘤细胞中，SMAC/DIABLO从线粒体的释放减少，这可能源于BCL2家族对线粒体通透性的稳定作用。
6. 转录因子NF-κB、丝裂原活化蛋白激酶（MAPK）以及细胞外调节激酶（ERK）1和2通路分别是IAP和BCL2家族的主要调控因子。
7. 这些发现为理解黑色素瘤细胞的凋亡抗性机制提供了 insights，并为基于促凋亡刺激和降低抗凋亡机制的治疗策略建立了理论框架。

英文摘要：

At the doses used clinically, chemotherapy is believed to kill melanoma by a final common 'mitochondrial' pathway that leads to apoptosis. Similarly, several natural defence mechanisms kill melanoma by the same pathways. A corollary to the latter is that survival of melanoma in the host is due to the development of anti-apoptotic mechanisms in melanoma cells. What are these mechanisms? And how might we bypass them to improve the treatment of melanoma?

摘要翻译： 

在临床使用剂量下，化疗被认为通过最终共同的"线粒体"通路导致黑色素瘤细胞凋亡。类似地，几种天然防御机制也通过相同途径杀灭黑色素瘤。由此可推论：黑色素瘤在宿主体内存活的原因在于瘤细胞形成了抗凋亡机制。这些机制具体是什么？我们该如何绕过这些机制以改善黑色素瘤的治疗？

原文链接：

How melanoma cells evade trail-induced apoptosis