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The sodium pump α1 subunit regulates bufalin sensitivity of human glioblastoma cells through the p53 signaling pathway

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Abstract

Bufalin is the primary component of the traditional Chinese medicine “Chan Su,” which has been widely used for cancer treatment at oncology clinics in certain countries. Evidence suggests that this compound possesses potent antitumor activities, although the exact molecular mechanism(s) require further elucidation. Therefore, this study aimed to further clarify the in vitro and in vivo antiglioma effects of bufalin and the molecular mechanism underlying the regulation of drug sensitivity. The anticancer effects of bufalin were determined by colony formation assays, apoptosis assays, and cellular redox state tests of glioma cells. Confocal microscopy was performed to determine the expression changes of the DNA damage biomarker γ-H2AX and the nuclear translocation of p53 in glioma cells. Western blotting and RT-PCR were used to detect the protein and gene expression levels, respectively. Here, we report that bufalin induced glioblastoma cell apoptosis and oxidative stress and triggered DNA damage. The critical roles of the sodium pump α1 subunit (ATP1A1) in mediating the XPO1-targeted anticancer effect of bufalin in human glioma were further confirmed. Mechanistic studies confirmed the important roles of Src and p53 signaling in mediating bufalin-induced apoptosis. Importantly, bufalin also inhibited the growth of glioma xenografts. In conclusion, our study indicated that therapies targeting the ATP1A1 and p53 signaling-mediated mitochondrial apoptotic pathways regulated by bufalin might be potential treatments for human glioma, and these findings will provide molecular bases for developing bufalin into a drug candidate for the treatment of malignant glioma.

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Funding

This work is supported by grants from the National Natural Science Foundation of China (Nos. 81372714, 81672480), Liaoning Provincial Natural Science Foundation of China (No. 201602244), Distinguished Professor Project of Liaoning Province, Special Grant for Translational Medicine, Dalian Medical University (No. 2015002), and Basic Research Projects in Colleges and Universities of Liaoning Province (No. LQ2017033).

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  1. Yu-Long Lan, Yu-Jie Zou and Jia-Cheng Lou contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China

    Yu-Long Lan, Jia-Cheng Lou, Jin-Shan Xing, Xun Wang, Bin-Bin Ma & Bo Zhang

  2. Department of Neurosurgery, Shenzhen People’s Hospital, Shenzhen, China

    Yu-Long Lan & Bo Zhang

  3. Department of Pharmacy, Dalian Medical University, Dalian, 116044, China

    Yu-Long Lan

  4. Department of Physiology, Dalian Medical University, Dalian, 116044, China

    Yu-Long Lan & Shuang Zou

  5. Department of Nursing, The First Affiliated Hospital of Dalian Medical University, Dalian, 116023, China

    Yu-Jie Zou

  6. Department of Pediatrics, Children’s Hospital of Boston, Harvard Medical School, Boston, MA, 02115, USA

    Yan Ding

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  1. Yu-Long Lan
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Contributions

BZ and YD conceived and supervised the study and revised the manuscript; YLL, YJZ, and JCL designed and performed the experiments, analyzed the data, and drafted the manuscript; and JSX, XW, SZ, and BBM collected data and revised the manuscript.

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Correspondence to Yan Ding or Bo Zhang.

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Lan, YL., Zou, YJ., Lou, JC. et al. The sodium pump α1 subunit regulates bufalin sensitivity of human glioblastoma cells through the p53 signaling pathway. Cell Biol Toxicol 35, 521–539 (2019). https://doi.org/10.1007/s10565-019-09462-y

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