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.

  • Compound C18H26O5

    Ethyl 2-(3,5-dihydroxy-2-octanoylphenyl)acetate

  • Compound C15H22O4

    1-(3,4,5)-Trihydroxyphenyl)nonan-1-one

  • Compound C18H28O3

    1-(3,5-Dimethoxyphenyl)decan-1-one

  • Compound C7H6O5

    3,4,5-Trihydroxybenzoic acid

  • Compound C10H12O5

    3,4,5-Trimethoxybenzoic acid

  • Compound C12H17NO5

    N,3,4,5-Tetramethoxy-N-methylbenzamide

  • Compound C18H28O4

    1-(3,4,5-Trimethoxyphenyl)nonan-1-one

  • Compound C7H6O4

    3,5-Dihydroxybenzoic acid

  • Compound C9H10O4

    3,5-Dimethoxybenzoic acid

  • Compound C11H15NO4

    N,3,5-Trimethoxy-N-methylbenzamide

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Acknowledgements

We thank L. Yu from Tsinghua University; S.C. Lin from Xiamen University; and Q. Chen from the Institute of Zoology, Chinese Academy of Science, China for their critical suggestions. We would like to thank G.Q. Wang from the Zhongshan Hospital of Xiamen University for providing MeWo melanoma cells. This work was supported by grants from the National Natural Science Fund of China and the '973' Project of the Ministry of Science and Technology (31230019, 2014CB910602, 31370724, 31221065 and 30971525); the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2012KF002); and the 111 Project of Education of China (no. B06016). The crystallographic data collection at Beamline BL17U1 at Shanghai Synchrotron Radiation Facility is gratefully acknowledged.

Author information

Author notes

    • Wei-jia Wang
    • , Yuan Wang
    • , Hang-zi Chen
    • , Yong-zhen Xing
    •  & Feng-wei Li

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian Province, China.

    • Wei-jia Wang
    • , Yuan Wang
    • , Hang-zi Chen
    • , Yong-zhen Xing
    • , Feng-wei Li
    • , Qian Zhang
    • , Bo Zhou
    • , Xue-li Bian
    • , Li Li
    • , Yuan Liu
    • , Bi-xing Zhao
    • , Yan Chen
    • , Rong Wu
    • , An-zhong Li
    • , Lu-ming Yao
    • , Ping Chen
    • , Yi Zhang
    • , Xu-yang Tian
    • , Jiahuai Han
    • , Tianwei Lin
    •  & Qiao Wu
  2. Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian Province, China.

    • Hong-kui Zhang
    • , Jie Zhang
    •  & Pei-qiang Huang
  3. ISREC, Swiss Institute for Experimental Cancer Research, SV EPFL, Lausanne, Switzerland.

    • Friedrich Beermann
  4. Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, China.

    • Mian Wu

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Contributions

Q.W.'s laboratory (W.-j.W., Y.W., H.-z.C., Y.-z.X., B.Z., X.-l.B., L.L., Y.L., B.-x.Z., Y.C., R.W. and Y.Z.) was responsible for the experiments on molecular cellular biology and mouse detections. Lin's laboratory (F.-w.L., Q.Z., A.-z.L. and X.-y.T.) was responsible for the structure determination and analysis. P.-q.H.'s laboratory (H.-k.Z. and J.Z.) provided the compounds. L.-m.Y. and P.C. provided the electron microscopic technique and images. F.B. provided the mouse model of autochthonous melanoma in the skin. M.W. provided melanoma cell lines Mel-11, ME4405, Mel-RM, MM200 and IgR3. J.H. and M.W. were involved in the design of this project as well as in reading and commenting on the manuscript. Q.W. and T.L. designed the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tianwei Lin or Qiao Wu.

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https://doi.org/10.1038/nchembio.1406

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