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The homeostasis-maintaining metabolites from bacterial stress response to bacteriophage infection suppress tumor metastasis

Oncogene volume 37, pages 5766–5779 (2018)Cite this article

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Abstract

The antiviral metabolites from bacterial stress response to bacteriophage infection can maintain homeostasis of host cells, while metabolism disorder is a remarkable characteristic of tumorigenesis. In the aspect of metabolic homeostasis, therefore, the antiviral homeostasis-maintaining metabolites of bacteria may possess anti-tumor activity. However, this issue has not been addressed. Here we show that the homeostasis-challenged maintaining metabolites from deep-sea bacteriophage-challenged thermophile can suppress tumor metastasis. The results indicated that the metabolic profiles of the bacteriophage GVE2-infected and virus-free thermophile Geobacillus sp. E263 from a deep-sea hydrothermal vent were remarkably different. Thirteen metabolites were significantly elevated and two metabolites were downregulated in thermophile stress response to GVE2 infection. As an example, the upregulated L-norleucine was characterized. The data showed that L-norleucine had antiviral activity in thermophile. Furthermore, the in vitro and in vivo assays revealed that L-norleucine, as well as its derivative, significantly suppressed metastasis of gastric and breast cancer cells. L-norleucine interacted with hnRNPA2/B1 protein to inhibit the expressions of Twist1 and Snail, two inhibitors of E-cadherin, and promote the E-cadherin expression, leading to the inhibition of tumor metastasis. Therefore, our study presented that antiviral homeostasis-maintaining metabolites of microbes might be a promising source for anti-tumor drugs.

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Acknowledgements

Funding:

This work was supported by China Ocean Mineral Resources R & D Association (DY135-B-04) and National Program on the Key Basic Research Project (2015CB755903).

Author contributions

XZ conceived the idea, XZ, TH, MJ, and CX designed the experiments. TH, MJ, and CX did the experiments. FW and ZM synthesized the derivatives of L-norleucine. TH and XZ wrote the paper. All authors reviewed the paper.

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Authors and Affiliations

  1. College of Life Sciences, Zhejiang University, 310058, Hangzhou, People’s Republic of China

    Tianliang He, Min Jin, Chenxi Xu & Xiaobo Zhang

  2. Department of Ocean Science and Engineering, Institute of Marine Biology and Natural Products, Zhejiang University, 310058, Hangzhou, People’s Republic of China

    Zhongjun Ma

  3. School of Chemistry and Materials Engineering, Fuyang Normal University, 236037, Fuyang, People’s Republic of China

    Fufang Wu

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  1. Tianliang He
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Correspondence to Xiaobo Zhang.

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All animal experiments were conducted in compliance with the Institutional Animal Care and Use Committee (IACUC) guidelines of Zhejiang University.

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He, T., Jin, M., Xu, C. et al. The homeostasis-maintaining metabolites from bacterial stress response to bacteriophage infection suppress tumor metastasis. Oncogene 37, 5766–5779 (2018). https://doi.org/10.1038/s41388-018-0376-z

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