Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany.
Merck Serono TA Oncology, Merck KGaA, Frankfurter Str. 250, Darmstadt D-64293, Germany.
Cell Death Dis. 2017 Oct 5;8(10):e3069. doi: 10.1038/cddis.2017.466.
Disruption of the Golgi apparatus can induce a distinct form of programmed cell death that has not been thoroughly characterized. We found that pharmacological application of Golgi stress leads to induction of death receptors (DRs) 4 and 5. DR4 appears to be primarily responsible for the initiation of cell death downstream of Golgi stress, whereas DR5 seems to be more important for cell death triggered by endoplasmic reticulum (ER) stress in specific cancer cell lines. DR induction downstream of either Golgi or ER stress mainly causes intracellular accumulation of DR4 presumably at the Golgi, rather than increased expression on the cell surface. Nevertheless, cells treated with secretory pathway stressors displayed an increased susceptibility to TRAIL (tumor necrosis factor related apoptosis inducing ligand), the endogenous ligand of DR4/5, probably due to intracellular sequestration of the caspase-8 regulator CFLAR (caspase-8 and FADD-like apoptosis regulator). These findings have implications for the treatment of cancer with DR agonists and our general understanding of DR signaling while highlighting the role of the Golgi apparatus as a cell death signaling platform.
高尔基氏体的功能紊乱可诱导一种尚未被充分描述的特殊形式的细胞程序性死亡。我们发现，通过药理学手段对高尔基氏体施加压力会导致死亡受体（DR）4 和 5 的诱导。DR4 似乎主要负责高尔基氏体压力下游细胞死亡的启动，而 DR5 似乎对于内质网（ER）应激在特定癌细胞系中引发的细胞死亡更为重要。无论在高尔基氏体还是 ER 应激的下游诱导 DR，主要会导致 DR4 在高尔基氏体中的细胞内积累，而不是细胞表面表达增加。然而，用分泌途径应激因子处理的细胞对 TRAIL（肿瘤坏死因子相关凋亡诱导配体）的敏感性增加，DR4/5 的内源性配体，这可能是由于半胱天冬酶-8 调节剂 CFLAR（半胱天冬酶-8 和 FADD 样凋亡调节剂）的细胞内隔离。这些发现对用 DR 激动剂治疗癌症以及我们对 DR 信号的一般理解具有重要意义，同时强调了高尔基氏体作为细胞死亡信号平台的作用。
