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Src inhibition induces mitotic arrest associated with chromosomal passenger complex

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Abstract

The non-receptor tyrosine kinase Src plays a key role in cell division, migration, adhesion, and survival. Src is overactivated in several cancers, where it transmits signals that promote cell survival, mitosis, and other important cancer hallmarks. Src is therefore a promising target in cancer therapy, but the underlying mechanisms are still uncertain. Here we show that Src is highly conserved across different species. Src expression increases during mitosis and is localized to the chromosomal passenger complex. Knockdown or inhibition of Src induces multipolar spindle formation, resulting in abnormal expression of the Aurora B and INCENP components of the chromosomal passenger complex. Molecular mechanism studies have found that Src interacts with and phosphorylates INCENP. This then leads to incorrect chromosome arrangement and segregation, resulting in cell division failure. Herein, Src and chromosomal passenger complex co-localize and Src inhibition impedes mitotic progression by inducing multipolar spindle formation. These findings provide novel insights into the molecular basis for using Src inhibitors to treat cancer.

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Data availability

The data that support the findings of this study are available from the corresponding author D.L., upon reasonable request.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2021YFA1101001), the National Natural Science Foundation of China (32070787 and 32000870) and the China Postdoctoral Science Foundation (2022M711923). The work was also supported by Science and Technology Fund of Tianjin First Central Hospital (2020CM03) and Tianjin Health Science and technology project (ZC20061). We thank Dr. Yijun Zhang from Nankai University for the revision of this manuscript.

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Authors and Affiliations

  1. Department of Cell Biology School of Basic Medical Sciences Cheeloo College of Medicine, Shandong University, Jinan, China

    Song Yang & Yunfan Yang

  2. State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China

    Youguang Luo, Mulin Yang, Hua Ni, Hanxiao Yin, Jun Zhou & Dengwen Li

  3. Department of Otorhinolaryngology Head and Neck Surgery, Tianjin First Central Hospital, Tianjin, China

    Ming Hu

  4. Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Collaborative Innovation Center of Cell Biology, Universities of Shandong, Shandong Normal University, Jinan, China

    Min Liu & Jun Zhou

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  1. Song Yang
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Contributions

S.Y. performed most of the experiments, analyzed data, and wrote the manuscript. Y.L., M.Y., H.N. and H.Y. contributed to experiments. J.Z., M.H., M.L. and Y.Y. provided advice on the manuscript. J.Z., Y.L. and D.L. designed experiments, supervised the study, and wrote the manuscript.

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Correspondence to Youguang Luo or Dengwen Li.

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Yang, S., Luo, Y., Yang, M. et al. Src inhibition induces mitotic arrest associated with chromosomal passenger complex. Cell Tissue Res 392, 733–743 (2023). https://doi.org/10.1007/s00441-023-03765-7

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