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DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway

Oncogene volume 40, pages 5579–5589 (2021)Cite this article

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Abstract

We have previously reported that the differentiation-inducing factor-1 (DIF-1), a compound identified in Dictyostelium discoideum, suppresses the growth of MCF-7 breast cancer cells by inactivating p70 ribosomal protein S6 kinase (p70S6K). Therefore, we first examined whether the same mechanism operates in other breast cancer cells, especially triple-negative breast cancer (TNBC), the most aggressive and refractory phenotype of breast cancer. We also investigated the mechanism by which DIF-1 suppresses p70S6K by focusing on the AMPK-mTORC1 system. We found that DIF-1 induces phosphorylation of AMPK and Raptor and dephosphorylation of p70S6K in multiple TNBC cell lines. Next, we examined whether AMPK-mediated inhibition of p70S6K leads to the suppression of proliferation and migration/infiltration of TNBC cells. DIF-1 significantly reduced the expression levels of cyclin D1 by suppressing the translation of STAT3 and strongly suppressed the expression levels of Snail, which led to the suppression of growth and motility, respectively. Finally, we investigated whether DIF-1 exerts anticancer effects on TNBC in vivo. Intragastric administration of DIF-1 suppressed tumor growth and spontaneous lung metastasis of 4T1-Luc cells injected into the mammary fat pad of BALB/c mice. DIF-1 is expected to lead to the development of anticancer drugs, including anti-TNBC, by a novel mechanism.

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Fig. 1: The effect of DIF-1 on the AMPK-mTORC1-S6K signaling pathway in breast cancer cell lines.
Fig. 2: Involvement of AMPK in the DIF-1-induced inactivation of S6K.
Fig. 3: Role of mTORC1 in the signaling pathway for cell proliferation.
Fig. 4: Involvement of STAT3 in the DIF-1-induced suppression of cyclin D1 expression and cell proliferation.
Fig. 5: Mechanism for the DIF-1-induced suppression of STAT3 expression.
Fig. 6: DIF-1-induced inhibition of Snail-mediated cell motility.
Fig. 7: DIF-1-induced prevention of in vivo tumor growth and spontaneous metastasis of 4T1-Luc cells.
Fig. 8: Current hypothesis on the mechanism of DIF-1’s action.

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Acknowledgements

We appreciate the technical support provided by the Research Support Center at the Graduate School of Medical Sciences of Kyushu University. This study was supported by JSPS KAKENHI Grant Numbers JP17K15581, JP20K07292, JP20K22709, by Fukuoka Foundation for Sound Health Cancer Research Fund to MA, by Kaibara Morikazu Medical Science Promotion Foundation to MA, and by Society for Women’s Health Science Research to FTY.

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  1. Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Fumi Seto-Tetsuo, Masaki Arioka, Koichi Miura, Takeru Inoue & Toshiyuki Sasaguri

  2. Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga, Japan

    Kazunobu Igawa & Katsuhiko Tomooka

  3. Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan

    Fumi Takahashi-Yanaga

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  1. Fumi Seto-Tetsuo
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Seto-Tetsuo, F., Arioka, M., Miura, K. et al. DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway. Oncogene 40, 5579–5589 (2021). https://doi.org/10.1038/s41388-021-01958-4

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