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The interaction between lipocalin 2 and dipyridine ketone hydrazone dithiocarbamte may influence respective function in proliferation and metastasis-related gene expressions in HepG2 cell

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Abstract

LCN2 (Lipocalins) was first identified as iron transporter through associating with its siderophores and also involved in many cancer metastases, but its function is still paradoxical. We questioned that whether LCN2 might also associate exogenous iron chelator as does in inherent way and the association may influence their respective function. To address this issue, we investigated the effect of LCN2 on action of DpdtC (2,2′-dipyridine ketone hydrazone dithiocarbamte), an iron chelator in proliferation and metastasis-related gene expression. The results showed that exogenous LCN2 and DpdtC could inhibit growth of HepG2 cells, while the combination treatment enhanced their inhibitory effect both in proliferation and colony formation. This encouraged us to investigate the effect of the interaction on metastasis-related gene expression. The results revealed that both LCN2 and DpdtC impaired the wound healing of HepG2, but the inhibitory effect of DpdtC was significantly enhanced upon association with LCN2. Undergoing epithelium-mesenchymal transition (EMT) is a crucial step for cancer metastasis, LCN2 and DpdtC had opposite effects on EMT markers, the binding of DpdtC to LCN2 significantly weakened the regulation of it (or its iron chelate) on EMT markers. To insight into the interaction between LCN2 and DpdtC–iron, fluorescence titration and molecular docking were performed to obtain the association constant (~ 104 M−1) and thermodynamic parameters (ΔG = − 26.10 kJ/mol). Importantly this study provided evidence that siderophores-loading state of LCN2 may influence its function, which be helpful for understanding the contradictory role of LCN2 in the metastasis of cancer.

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Acknowledgments

This study was supported through grants awarded by the National Natural Science Foundation of China (No. 21571153)and Xinxiang Medical University (provincial) college students' innovation and entrepreneurship project (202010472036).

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  1. Cuiping Li, and Yongli Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Xinxiang Medical University, Xinxiang, 453003, Henan, People’s Republic of China

    Cuiping Li, Liying Lou, Xinyi Han, Huihui Wang, Tengfei Huang & Changzheng Li

  2. Department of Histology and Embryology, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, Henan, People’s Republic of China

    Yongli Li

  3. Experimental Teaching Center of Biology and Basic Medical Sciences, Sanquan College of Xinxiang Medical University, Xinxiang, 453003, Henan, People’s Republic of China

    Changzheng Li

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  1. Cuiping Li
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Contributions

CL and YL performed the main experiments; they contributed equally to this work. Changzheng Li conceived and designed the experiments. LL, XH, and HW performed part experiments and data analysis. Tengfei Huang prepared the iron chelator. CL prepared and wrote the paper.

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Correspondence to Changzheng Li.

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Li, C., Li, Y., Lou, L. et al. The interaction between lipocalin 2 and dipyridine ketone hydrazone dithiocarbamte may influence respective function in proliferation and metastasis-related gene expressions in HepG2 cell. J Biol Inorg Chem 26, 123–133 (2021). https://doi.org/10.1007/s00775-020-01842-8

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