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

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 (p70 ). Therefore, we first examined whether the same mechanism operat...

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Bibliographic Details
Published in:Oncogene 2021-09, Vol.40 (37), p.5579-5589
Main Authors: Seto-Tetsuo, Fumi, Arioka, Masaki, Miura, Koichi, Inoue, Takeru, Igawa, Kazunobu, Tomooka, Katsuhiko, Takahashi-Yanaga, Fumi, Sasaguri, Toshiyuki
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
Animals
Antineoplastic drugs
Antitumor agents
Biomolecules
Birds of prey
Breast cancer
Cell migration
Cell proliferation
Cellular signal transduction
Cyclin D1
Dephosphorylation
Development and progression
Drug development
Genetic aspects
Health aspects
Humans
Kinases
Mechanistic Target of Rapamycin Complex 1
Metastases
Metastasis
Mice
Phenotypes
Phosphorylation
Protein kinases
Ribosomal protein S6
Ribosomal protein S6 kinase
Ribosomal Protein S6 Kinases, 70-kDa
Signal Transduction
Stat3 protein
Triple Negative Breast Neoplasms
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Summary: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 (p70 ). 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 p70 by focusing on the AMPK-mTORC1 system. We found that DIF-1 induces phosphorylation of AMPK and Raptor and dephosphorylation of p70 in multiple TNBC cell lines. Next, we examined whether AMPK-mediated inhibition of p70 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.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-021-01958-4