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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Chudnovsky, Y., Khavari, P.A. & Adams, A.E. Melanoma genetics and the development of rational therapeutics. J. Clin. Invest. 115, 813–824 (2005).
Gray-Schopfer, V., Wellbrock, C. & Marais, R. Melanoma biology and new targeted therapy. Nature 445, 851–857 (2007).
Flaherty, K.T., Hodi, F.S. & Fisher, D.E. From genes to drugs: targeted strategies for melanoma. Nat. Rev. Cancer 12, 349–361 (2012).
Soengas, M.S. & Lowe, S.W. Apoptosis and melanoma chemoresistance. Oncogene 22, 3138–3151 (2003).
Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).
Maiuri, M.C., Zalckvar, E., Kimchi, A. & Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8, 741–752 (2007).
Yu, L., Strandberg, L. & Lenardo, M.J. The selectivity of autophagy and its role in cell death and survival. Autophagy 4, 567–573 (2008).
Youle, R.J. & Narendra, D.P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).
Novak, I. et al. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11, 45–51 (2010).
Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).
Zabirnyk, O., Liu, W., Khalil, S., Sharma, A. & Phang, J.M. Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy. Carcinogenesis 31, 446–454 (2010).
Wang, J., Lian, H., Zhao, Y., Kauss, M.A. & Spindel, S. Vitamin D3 induces autophagy of human myeloid leukemia cells. J. Biol. Chem. 283, 25596–25605 (2008).
Wang, R.H. et al. The orphan receptor TR3 participates in angiotensin II–induced cardiac hypertrophy by controlling mTOR signalling. EMBO Mol. Med. 5, 137–148 (2013).
Chen, H.Z. et al. The orphan receptor TR3 suppresses intestinal tumorigenesis in mice by downregulating Wnt signalling. Gut 61, 714–724 (2012).
Zhao, B.X. et al. Orphan receptor TR3 enhances p53 transactivation and represses DNA double-strand break repair in hepatoma cells under ionizing radiation. Mol. Endocrinol. 25, 1337–1350 (2011).
Chen, H.Z. et al. Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis. Oncogene 31, 2876–2887 (2012).
Zhan, Y. et al. Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat. Chem. Biol. 4, 548–556 (2008).
Liu, J.J. et al. A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res. 70, 3628–3637 (2010).
Zhan, Y.Y. et al. The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nat. Chem. Biol. 8, 897–904 (2012).
Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011).
Declercq, W., Vanden Berghe, T. & Vandenabeele, P. RIP kinases at the crossroads of cell death and survival. Cell 138, 229–232 (2009).
Green, D.R. Apoptotic pathways: ten minutes to dead. Cell 121, 671–674 (2005).
Modjtahedi, N., Giordanetto, F., Madeo, F. & Kroemer, G. Apoptosis-inducing factor: vital and lethal. Trends Cell Biol. 16, 264–272 (2006).
Chen, H.Z. et al. Akt phosphorylates the TR3 orphan receptor and blocks its targeting to the mitochondria. Carcinogenesis 29, 2078–2088 (2008).
Lin, B. et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116, 527–540 (2004).
Zhang, J. & Ney, P.A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 16, 939–946 (2009).
Narendra, D., Tanaka, A., Suen, D.F. & Youle, R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).
Kroemer, G., Galluzzi, L. & Brenner, C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87, 99–163 (2007).
Jin, S.M. et al. Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J. Cell Biol. 191, 933–942 (2010).
Baker, M.J., Frazier, A.E., Gulbis, J.M. & Ryan, M.T. Mitochondrial protein-import machinery: correlating structure with function. Trends Cell Biol. 17, 456–464 (2007).
Zhan, Y.Y. & Wu, Q. Translocation of orphan receptor TR3 from nuclei to mitochondria induced by staurosporine. Ai Zheng 23, 1593–1598 (2004).
Rosenfeldt, M.T. & Ryan, K.M. The multiple roles of autophagy in cancer. Carcinogenesis 32, 955–963 (2011).
Tormo, D. et al. Targeted activation of innate immunity for therapeutic induction of autophagy and apoptosis in melanoma cells. Cancer Cell 16, 103–114 (2009).
Ackermann, J. et al. Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Cancer Res. 65, 4005–4011 (2005).
Yu, H., Kumar, S.M., Fang, D., Acs, G. & Xu, X. Nuclear orphan receptor TR3/Nur77 mediates melanoma cell apoptosis. Cancer Biol. Ther. 6, 405–412 (2007).
Sandoval, H. et al. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454, 232–235 (2008).
Baker, K.D. et al. The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell 113, 731–742 (2003).
Wang, Z. et al. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423, 555–560 (2003).
Rambold, A.S. & Lippincott-Schwartz, J. Mechanisms of mitochondria and autophagy crosstalk. Cell Cycle 10, 4032–4038 (2011).
Vaseva, A.V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536–1548 (2012).
Moll, U.M., Marchenko, N. & Zhang, X.K. p53 and Nur77/TR3—transcription factors that directly target mitochondria for cell death induction. Oncogene 25, 4725–4743 (2006).
Vogelzang, N.J. et al. Clinical cancer advances 2011: annual report on progress against cancer from the American society of clinical oncology. J. Clin. Oncol. 30, 88–109 (2012).
Sosman, J.A. et al. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012).
Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
Chung, H. et al. Ethambutol-induced toxicity is mediated by zinc and lysosomal membrane permeabilization in cultured retinal cells. Toxicol. Appl. Pharmacol. 235, 163–170 (2009).
Noonan, J. et al. Endocannabinoids prevent β-amyloid–mediated lysosomal destabilization in cultured neurons. J. Biol. Chem. 285, 38543–38554 (2010).
McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).
Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).
Collaborative Computational Project, Number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 50, 760–763 (1994).
Murshudov, G.N. et al. REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr. D Biol. Crystallogr. 67, 355–367 (2011).
Murshudov, G.N., Vagin, A.A. & Dodson, E.J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240–255 (1997).
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
Authors and Affiliations
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Results, Supplementary Figures 1–7, Supplementary Tables 1 and 2 and Supplementary Note. (PDF 3055 kb)
Rights and permissions
About this article
Cite this article
Wang, Wj., Wang, Y., Chen, Hz. et al. Orphan nuclear receptor TR3 acts in autophagic cell death via mitochondrial signaling pathway. Nat Chem Biol 10, 133–140 (2014). https://doi.org/10.1038/nchembio.1406
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchembio.1406
This article is cited by
-
Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P
Cell Research (2023)
-
Targeting lectin-like oxidized low-density lipoprotein receptor-1 triggers autophagic program in esophageal cancer
Cell Death & Differentiation (2022)
-
Prostaglandin A2 Interacts with Nurr1 and Ameliorates Behavioral Deficits in Parkinson’s Disease Fly Model
NeuroMolecular Medicine (2022)
-
Mitochondrial metabolism as a target for acute myeloid leukemia treatment
Cancer & Metabolism (2021)
-
BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease
Cell Death & Disease (2021)