1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
Nat Chem Biol. 2014 Feb;10(2):133-40. doi: 10.1038/nchembio.1406. Epub 2013 Dec 8.
Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1-VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.
自噬与细胞死亡有关，但相关机制在很大程度上尚未得到充分描述。我们发现，黑色素瘤通常对药物诱导的细胞凋亡具有抗性，但在孤儿核受体 TR3 的参与下，可以发生自噬性细胞死亡。一种特定的化学化合物 1-(3,4,5-三羟基苯基)壬烷-1-酮，通过筛选 TR3 靶向化合物库获得，引发了一系列导致细胞死亡的分子事件。自噬级联反应包括 TR3 通过与线粒体外膜蛋白 Nix 相互作用转移到线粒体，通过 Tom40 和 Tom70 通道蛋白穿过线粒体内膜，通过 ANT1-VDAC1 通透性转换孔复合物耗散线粒体膜电位，并诱导自噬。这个过程导致过多的线粒体清除和不可逆转的细胞死亡。它通过激活一条线粒体信号通路为黑色素瘤治疗提供了一种新的方法，该通路将核受体与自噬结合以诱导细胞死亡。
