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The Chk2-PKM2 axis promotes metabolic control of vasculogenic mimicry formation in p53-mutated triple-negative breast cancer

Oncogene volume 40, pages 5262–5274 (2021)Cite this article

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Abstract

Vasculogenic mimicry (VM) formation, which participates in the process of neovascularization, is highly activated in p53-mutated triple-negative breast cancer (TNBC). Here, we show that Chk2 is negatively correlated with VM formation in p53-mutated TNBC. Its activation by DNA-damaging agents such as cisplatin, etoposide, and DPT reduces VM formation. Mechanistically, the Chk2-PKM2 axis plays an important role in the inhibition of VM formation at the level of metabolic regulation. Chk2 promotes the Chk2-PKM2 interaction through the Chk2 SCD (SQ/TQ cluster domain) and the PKM2 C domain. Furthermore, Chk2 promotes the nuclear export of PKM2 by phosphorylating PKM2 at Ser100. P-PKM2 S100 reduces VM formation by decreasing glucose flux, and the PKM2 S100A mutation abolishes the inhibition of glucose flux and VM formation induced by Chk2 activation. Overall, this study proposes a novel strategy of VM suppression through Chk2 induction, which prevents PKM2-mediated glucose flux in p53-mutated TNBC.

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Fig. 1: A lower level of Chk2 was associated with increased VM formation in p53-mutated TNBC.
Fig. 2: Chk2 activation reduced VM formation in p53-mutated TNBC cells.
Fig. 3: Chk2 activation inhibited VM formation in Matrigel plugs and a xenograft model in vivo.
Fig. 4: Chk2 activation was required for the interaction between PKM2 and Chk2.
Fig. 5: Chk2 phosphorylates PKM2 at Ser100 and promotes its nuclear export.
Fig. 6: P-PKM2 S100 reduced glucose flux and VM formation.
Fig. 7: Chk2 activation inhibited PKM2-mediated glucose flux and VM formation.
Fig. 8: A schematic diagram of the proposed mechanism.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872986, 81872889), the “Double First-Class” University project (CPU2018GF03), the 111 Project from the Ministry of Education of China, and the State Administration of Foreign Export Affairs of China (B18056), the Drug Innovation Major Project (2018ZX09711-001-007, 2018ZX09735002-003).

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  1. Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China

    Pei Yu, Jia-Le Zhu, Yu-Bao Han, Hao Zhang, Lei Yang, Yuan-Zheng Xia, Chao Zhang & Ling-Yi Kong

  2. Medical and Chemical Institute, China Pharmaceutical University, Nanjing, China

    Xiong Zhu

  3. Department of Science, China Pharmaceutical University, Nanjing, China

    Xiang Zhou

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LK, PY, and CZ conceived and designed the project. PY, JZ, and YH performed the experiments and conducted the data analysis. PY and CZ wrote the paper. XZ and LY helped with experiments. CZ, HZ, XZ, and YX revised the manuscript.

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Yu, P., Zhu, X., Zhu, JL. et al. The Chk2-PKM2 axis promotes metabolic control of vasculogenic mimicry formation in p53-mutated triple-negative breast cancer. Oncogene 40, 5262–5274 (2021). https://doi.org/10.1038/s41388-021-01933-z

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