Journal Article

Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway

Chen, Hang-zi, Yao, Lu-ming, Li, An-zhong, Wang, Yuan, Zhang, Yi, Tian, Xu-yang, Chen, Yan, Xing, Yong-zhen, Bian, Xue-li, Lin, Tianwei, Zhang, Hong-kui, Han, Jiahuai, Li, Feng-wei, Li, Li, Beermann, Friedrich, Wu, Qiao, Wu, Mian, Zhang, Qian, Liu, Yuan, Chen, Ping, Zhou, Bo, Wu, Rong, Zhang, Jie, Huang, Pei-qiang, Zhao, Bi-xing, Wang, Wei-jia

2014

Overview

TR3 is an orphan nuclear receptor with roles in apoptosis. A TR3-binding compound induces mitochondrial translocation of TR3 and autophagy via the Nix–Toms–ANT1/VDAC1 pathway, providing a mechanism for cell death in melanoma cells that are resistant to spontaneous and drug-induced apoptosis. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/535/1266 / 631/67/1059 / 631/80/82 / 631/92/609 / 96 / Animals / Apoptosis / Autophagy / Binding sites / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Cell death / Cell Line, Tumor / Chemistry / Chemistry/Food Science / Crystallography, X-Ray / Disease Models, Animal / Humans / Ketones - chemistry / Ketones - pharmacology / Melanoma / Melanoma - drug therapy / Membrane Proteins - metabolism / Membranes / Mice / Mitochondria / Mitochondria - physiology / Mortality / Nuclear Receptor Subfamily 4, Group A, Member 1 - metabolism / Permeability / Protein Conformation / Proto-Oncogene Proteins - metabolism / Pyrogallol - analogs & derivatives / Pyrogallol - chemistry / Pyrogallol - pharmacology / Signal Transduction / Translocation / Tumor Suppressor Proteins - metabolism