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

Fumi Seto-Tetsuo, Masaki Arioka, Koichi Miura, Takeru Inoue, Kazunobu Igawa, Katsuhiko Tomooka, Fumi Takahashi, Toshiyuki Sasaguri

研究成果: ジャーナルへの寄稿学術誌査読

2 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)5579-5589
ページ数11
ジャーナルOncogene
40
37
DOI
出版ステータス出版済み - 9月 16 2021

!!!All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 癌研究

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