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Extracellular ATP promotes breast cancer invasion and chemoresistance via SOX9 signaling

Oncogene volume 39, pages 5795–5810 (2020)Cite this article

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Abstract

Our previous research demonstrated that extracellular adenosine 5′-triphosphate (ATP) could promote breast cancer cell invasion. However, the impact of extracellular ATP on chemoresistance and the mechanisms behind ATP pro-invasion and pro-chemoresistance remain unclear. Here we aimed to determine the molecules or signaling pathways involved. cDNA microarray was performed to identify the differentially expressed genes before and after ATP treatment. As a result, Sex-determining region Y-box 9 (SOX9) was up-regulated after ATP treatment in breast cancer cells. In vitro invasion and migration assays demonstrated that knocking down SOX9 attenuated ATP-driven invasive capability. Mass spectrometry and co-IP revealed that SOX9 interacted with Janus kinase 1 (JAK1). Afterward, IL-6-JAK1-STAT3 signaling was demonstrated to promote SOX9 expression and invasion following ATP treatment. Notably, ATP-IL-6-SOX9 signaling was shown to stimulate chemoresistance in breast cancer cells. ChIP assays identified some potential SOX9 target genes, among which carcinoembryonic antigen-related cell adhesion molecule 5/6 (CEACAM5/6) was demonstrated to mediate ATP pro-invasive function, while ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) mediated ATP-driven chemoresistance. In addition, SOX9-knockdown and apyrase (an ATP hydrolase)-treated MDA-MB-231 cells illustrated decreased tumor growth and enhanced drug sensitivity in nude mice. In vitro spheroid formation assays also proved the significance of ATP-SOX9 in mediating chemoresistance. Moreover, molecules involved in ATP-SOX9 signaling were up-regulated in human breast carcinoma specimens and were associated with poor prognosis. Altogether, SOX9 signaling is vital in ATP-driven invasion and chemoresistance, which may serve as a potential target for breast cancer therapies.

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Fig. 1: The up-regulation of SOX9 contributes to ATP-promoted breast cancer cell invasion in vitro.
Fig. 2: IL-6-JAK1-STAT3 is involved in ATP-SOX9 signaling and cancer cell invasion.
Fig. 3: IL-6-JAK1-STAT3-SOX9 axis is required for ATP-driven chemoresistance in breast cancer cells.
Fig. 4: ATP promotes invasion and chemoresistance via SOX9 targets CEACAM5/6, ABCB1, and ABCG2, respectively.
Fig. 5: ATP-SOX9 signaling promotes xenograft tumor growth, metastasis, and chemoresistance in vivo.
Fig. 6: ATP-SOX9 signaling mediates spheroid formation and chemoresistance in vitro.
Fig. 7: ATP-SOX9 axis is associated with clinical breast cancer progression.
Fig. 8: The proposed model for the ATP-SOX9 signaling.

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Acknowledgements

This work was supported by grants to XXT and WGF from the National Natural Science Foundation of China (No 81872382 and 81621063).

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  1. Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing 100191, China

    Hui Yang, Yue-Hang Geng, Han Yang, Yan-Ting Zhou, Hui-Ying He, Wei-Gang Fang & Xin-Xia Tian

  2. Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China

    Peng Wang & Hong-Quan Zhang

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Yang, H., Geng, YH., Wang, P. et al. Extracellular ATP promotes breast cancer invasion and chemoresistance via SOX9 signaling. Oncogene 39, 5795–5810 (2020). https://doi.org/10.1038/s41388-020-01402-z

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