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

• Published in: Oncogene Vol. 40; no. 37; pp. 5579 - 5589
• Main Authors: Seto-Tetsuo, Fumi, Arioka, Masaki, Miura, Koichi, Inoue, Takeru, Igawa, Kazunobu, Tomooka, Katsuhiko, Takahashi-Yanaga, Fumi, Sasaguri, Toshiyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-09-2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 13/89; 14/35; 631/154/555; 631/67/1059/153; 64/60; 82/80; 96/95; AMP-Activated Protein Kinases - metabolism; Animals; Antineoplastic drugs; Antitumor agents; Apoptosis; Biomolecules; Birds of prey; Breast cancer; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cellular signal transduction; Cyclin D1; Dephosphorylation; Development and progression; Drug development; Female; Genetic aspects; Health aspects; Hexanones - pharmacology; Human Genetics; Humans; Internal Medicine; Kinases; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 1 - metabolism; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Multiprotein Complexes - metabolism; Neoplasm Metastasis; Oncology; Phenotypes; Phosphorylation; Phosphorylation - drug effects; Protein kinases; Ribosomal protein S6; Ribosomal protein S6 kinase; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal transduction; Signal Transduction - drug effects; Stat3 protein; TOR Serine-Threonine Kinases - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Xenograft Model Antitumor Assays; Japan
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-021-01958-4

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
S6K
). 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
S6K
by focusing on the AMPK-mTORC1 system. We found that DIF-1 induces phosphorylation of AMPK and Raptor and dephosphorylation of p70
S6K
in multiple TNBC cell lines. Next, we examined whether AMPK-mediated inhibition of p70
S6K
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.