title: Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway.
abstract: 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.
authors: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
authors: Wei-jia
authors: WJ
authors: Wang
authors: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
authors: Yuan
authors: Y
authors: Wang
authors: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
authors: Hang-zi
authors: HZ
authors: Chen
authors: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
authors: Yong-zhen
authors: YZ
authors: Xing
authors: 1] State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China. [2].
authors: Feng-wei
authors: FW
authors: Li
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Qian
authors: Q
authors: Zhang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Bo
authors: B
authors: Zhou
authors: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
authors: Hong-kui
authors: HK
authors: Zhang
authors: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
authors: Jie
authors: J
authors: Zhang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Xue-li
authors: XL
authors: Bian
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Li
authors: L
authors: Li
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Yuan
authors: Y
authors: Liu
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Bi-xing
authors: BX
authors: Zhao
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Yan
authors: Y
authors: Chen
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Rong
authors: R
authors: Wu
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: An-zhong
authors: AZ
authors: Li
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Lu-ming
authors: LM
authors: Yao
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Ping
authors: P
authors: Chen
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Yi
authors: Y
authors: Zhang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Xu-yang
authors: XY
authors: Tian
authors: ISREC, Swiss Institute for Experimental Cancer Research, SV EPFL, Lausanne, Switzerland.
authors: Friedrich
authors: F
authors: Beermann
authors: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors: Mian
authors: M
authors: Wu
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Jiahuai
authors: J
authors: Han
authors: Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.
authors: Pei-qiang
authors: PQ
authors: Huang
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Tianwei
authors: T
authors: Lin
authors: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.
authors: Qiao
authors: Q
authors: Wu
mesh_terms: D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C587356:1-(3,4,5-trihydroxyphenyl)nonan-1-one; C116838:BNIP3L protein, human; D007659:Ketones; D008565:Membrane Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D011748:Pyrogallol