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Guo J, Cheng J, Zheng N, et al. Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner. Adv Sci (Weinh). 2021;8(18):e2004303doi: 10.1002/advs.202004303.
Guo, J., Cheng, J., Zheng, N., Zhang, X., Dai, X., Zhang, L., Hu, C., Wu, X., Jiang, Q., Wu, D., Okada, H., Pandolfi, P. P., & Wei, W. (2021). Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner. Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8(18), e2004303. https://doi.org/10.1002/advs.202004303
Guo, Jianping, et al. "Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner." Advanced science (Weinheim, Baden-Wurttemberg, Germany) vol. 8,18 (2021): e2004303. doi: https://doi.org/10.1002/advs.202004303
Guo J, Cheng J, Zheng N, Zhang X, Dai X, Zhang L, Hu C, Wu X, Jiang Q, Wu D, Okada H, Pandolfi PP, Wei W. Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner. Adv Sci (Weinh). 2021 Sep;8(18):e2004303. doi: 10.1002/advs.202004303. Epub 2021 Jul 18. PMID: 34278744; PMCID: PMC8456201.
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Adv Sci (Weinh). 2021 Sep;8(18):e2004303. doi: 10.1002/advs.202004303. Epub 2021 Jul 18.

Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

Jianping Guo, Ji Cheng, Nana Zheng, Xiaomei Zhang, Xiaoming Dai, Linli Zhang, Changjiang Hu, Xueji Wu, Qiwei Jiang, Depei Wu, Hitoshi Okada, Pier Paolo Pandolfi, Wenyi Wei

Affiliations

  1. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  2. Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China.
  3. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
  4. National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
  5. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  6. Department of Biochemistry, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
  7. Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

PMID: 34278744 PMCID: PMC8456201 DOI: 10.1002/advs.202004303

Abstract

Copper plays pivotal roles in metabolic homoeostasis, but its potential role in human tumorigenesis is not well defined. Here, it is revealed that copper activates the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB, also termed AKT) oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper binds 3-phosphoinositide dependent protein kinase 1 (PDK1), in turn promotes PDK1 binding and subsequently activates its downstream substrate AKT to facilitate tumorigenesis. Blocking the copper transporter 1 (CTR1)-copper axis by either depleting CTR1 or through the use of copper chelators diminishes the AKT signaling and reduces tumorigenesis. In support of an oncogenic role for CTR1, the authors find that CTR1 is abnormally elevated in breast cancer, and is subjected by NEDD4 like E3 ubiquitin protein ligase (Nedd4l)-mediated negative regulation through ubiquitination and subsequent degradation. Accordingly, Nedd4l displays a tumor suppressive function by suppressing the CTR1-AKT signaling. Thus, the findings identify a novel regulatory crosstalk between the Nedd4l-CTR1-copper axis and the PDK1-AKT oncogenic signaling, and highlight the therapeutic relevance of targeting the CTR1-copper node for the treatment of hyperactive AKT-driven cancers.

© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.

Keywords: AKT; CTR1; Nedd4l; PDK1; breast cancer; copper

References

  1. Leukemia. 2005 Apr;19(4):586-94 - PubMed
  2. Mol Pharmacol. 2009 Jan;75(1):174-82 - PubMed
  3. Oncogene. 2005 Feb 17;24(8):1477-80 - PubMed
  4. J Neurosci. 1999 Nov 1;19(21):9170-9 - PubMed
  5. J Biol Chem. 1994 Jan 28;269(4):2405-10 - PubMed
  6. J Histochem Cytochem. 2006 Sep;54(9):1041-9 - PubMed
  7. Nature. 1999 Sep 2;401(6748):82-5 - PubMed
  8. Structure. 2014 Nov 4;22(11):1639-49 - PubMed
  9. Biochem J. 2000 Mar 15;346 Pt 3:561-76 - PubMed
  10. Oncotarget. 2018 Jan 20;9(10):9325-9343 - PubMed
  11. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14298-302 - PubMed
  12. Toxicol Sci. 2011 Jan;119(1):3-19 - PubMed
  13. Curr Biol. 1997 Oct 1;7(10):776-89 - PubMed
  14. Anal Chem. 2015 Nov 3;87(21):10995-1006 - PubMed
  15. Cell Metab. 2016 Jan 12;23(1):27-47 - PubMed
  16. Nature. 2007 Feb 8;445(7128):661-5 - PubMed
  17. Cancer Res. 2002 Sep 1;62(17):4854-9 - PubMed
  18. Nat Rev Cancer. 2009 Aug;9(8):550-62 - PubMed
  19. Br J Pharmacol. 2005 Dec;146(8):1041-59 - PubMed
  20. Bioorg Chem. 2006 Aug;34(4):200-23 - PubMed
  21. Am J Clin Nutr. 2007 Jun;85(6):1586-91 - PubMed
  22. EXS. 2006;(96):97-130 - PubMed
  23. Clin Cancer Res. 2018 Sep 1;24(17):4271-4281 - PubMed
  24. Science. 1998 Jan 30;279(5351):710-4 - PubMed
  25. Nat Rev Cancer. 2007 Jul;7(7):519-30 - PubMed
  26. Biochem Pharmacol. 2012 Oct 15;84(8):1007-13 - PubMed
  27. Nat Rev Drug Discov. 2005 Dec;4(12):988-1004 - PubMed
  28. Biochim Biophys Acta. 2014 Jan;1843(1):61-74 - PubMed
  29. Mol Cell. 2009 Nov 13;36(3):457-68 - PubMed
  30. Ann Nucl Med. 2011 Jun;25(5):339-45 - PubMed
  31. Adv Sci (Weinh). 2021 Sep;8(18):e2004303 - PubMed
  32. Breast Cancer Res Treat. 2016 Dec;160(3):439-446 - PubMed
  33. Nature. 2014 Apr 24;508(7497):541-5 - PubMed
  34. Cancer Cell. 2003 Oct;4(4):257-62 - PubMed
  35. J Am Chem Soc. 2010 Nov 3;132(43):15351-8 - PubMed
  36. Annu Rev Med. 2016;67:11-28 - PubMed
  37. Nat Cell Biol. 2019 Feb;21(2):226-237 - PubMed
  38. Oncogene. 2005 Nov 14;24(50):7455-64 - PubMed
  39. Lung Cancer. 2014 Jul;85(1):88-93 - PubMed
  40. Nature. 2014 May 22;509(7501):492-6 - PubMed
  41. Science. 2016 Aug 26;353(6302):929-32 - PubMed
  42. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4279-88 - PubMed
  43. Metallomics. 2016 Sep 1;8(9):951-62 - PubMed
  44. Sci Signal. 2014 Jun 10;7(329):ra56 - PubMed
  45. EMBO J. 2003 Oct 15;22(20):5501-10 - PubMed
  46. Cell. 2000 Feb 18;100(4):387-90 - PubMed
  47. Mol Pharmacol. 2013 Jun;83(6):1237-46 - PubMed
  48. Curr Biol. 1997 Apr 1;7(4):261-9 - PubMed
  49. Cell. 2017 Apr 20;169(3):381-405 - PubMed
  50. Nat Chem Biol. 2016 Aug;12(8):586-92 - PubMed
  51. Nat Rev Mol Cell Biol. 2009 Jun;10(6):398-409 - PubMed
  52. J Biol Chem. 2003 Oct 31;278(44):42913-9 - PubMed
  53. Cell Discov. 2016 Feb 02;2:15044 - PubMed
  54. Traffic. 2007 Oct;8(10):1375-84 - PubMed
  55. Dev Biol. 2014 Aug 1;392(1):15-25 - PubMed
  56. Nat Cell Biol. 2020 Apr;22(4):412-424 - PubMed
  57. J Biol Chem. 2018 Mar 30;293(13):4628-4635 - PubMed

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