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Zinc ions activate AKT and promote prostate cancer cell proliferation via disrupting AKT intramolecular interaction

Oncogene volume 44, pages 8–18 (2025)Cite this article

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Abstract

Prostate is a zinc rich organ and the physiological function of the abundant zinc ions is relatively less understood. AKT kinase is a pivotal regulator downstream of cytokines, growth factors and other extracellular stimuli, and the attachment of its PH ___domain to PtdIns-3,4,5-P3 (PIP3) and the subsequent phosphorylation of its kinase ___domain by PDPK1 are considered important for its activation. Herein, we report a regulatory mechanism of AKT kinase by zinc ions. Mechanistically, zinc ions directly bind to AKT and facilitate AKT activation through disrupting the interaction between PH and kinase domains within AKT molecule. Consistently, AKT1-H89A/E91A mutant (zinc-binding-deficient) fails to respond to zinc ions and exhibits strong interaction between PH and kinase domains, and it is less oncogenic in orthotopic xenograft model of prostate cancer. On the other hand, the AKT1-W80L mutant with minimum intra-molecular interaction between PH and kinase domains shows strong tumor promoting capacity although it could not be further stimulated by zinc ions. Overall, this study reveals a distinctive regulatory mechanism of AKT activation and implies a tumor promoting role of the zinc ions in prostate cancer.

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Fig. 1: Zinc ions activate AKT kinase to promote prostate cancer cells growth.
Fig. 2: His89 and Glu91 are important for AKT activation by zinc ions.
Fig. 3: Binding to zinc ions results in disrupting intra-molecular interaction between PH and kinase domains of AKT.
Fig. 4: Zinc ions promote AKT cytoplasmic membrane translocation.
Fig. 5: Zinc ions bind to AKT to promote AKT-dependent prostate cancer progression in mice.

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Data availability

This study does not report any original code. All data generated in this study are presented in this paper and the Supplementary Materials files. Any information supporting this article is available from the lead contact upon reasonable request.

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Acknowledgements

We thank Dr. Dangsheng Li for kindly providing great helpful suggestions.

Funding

This work was supported by the National Key Research and Development Program of China (grants 2020YFA0803203, 2019YFA0802102), grants from National Natural Science Foundation of China (81925029, 81790253, 82230098, 32221002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19020203 and XDB37010303), and the CAS project for young scientists in basic research (YSBR-014) and Shanghai Municipal Science and Technology Major Project.

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Author notes

  1. These authors contributed equally: Kangjunjie Wang, Min Chen, Shukun Yan.

Authors and Affiliations

  1. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Kangjunjie Wang, Yong Chen & Daming Gao

  2. Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China

    Kangjunjie Wang, Huairui Yuan, Long Li, Kaihua Wang, Fen Liu, Qianqian Li & Daming Gao

  3. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203, Shanghai, China

    Min Chen

  4. University of Chinese Academy of Sciences, Number 19A Yuquan Road, Beijing, 100049, China

    Shukun Yan, Huairui Yuan, Fen Liu, Qianqian Li, Hu Zhou, Yong Chen, Jun Qin & Daming Gao

  5. Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China

    Shukun Yan & Yong Chen

  6. CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China

    Ying Han & Jun Qin

  7. Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, 400042, China

    Qiuli Liu, Jun Jiang & Jun Qin

  8. Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Dayun Lu & Hu Zhou

  9. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Dakui Luo

Authors
  1. Kangjunjie Wang
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  2. Min Chen
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Contributions

DG conceived the study. DG, JQ, and YC supervised the study with input from HZ. Kangjunjie W, MC, and SY performed the bench experiments and analyzed the data with assistance from YH, HY, LL, Kaihua W, FL, Qianqian L, Dakui L. Dayun L. Qiuli L and JJ collected and provided the clinical prostate samples. DG and Kangjunjie W wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Yong Chen, Jun Qin or Daming Gao.

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Wang, K., Chen, M., Yan, S. et al. Zinc ions activate AKT and promote prostate cancer cell proliferation via disrupting AKT intramolecular interaction. Oncogene 44, 8–18 (2025). https://doi.org/10.1038/s41388-024-03195-x

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