DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway
DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway
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DOI：
10.1038/s41388-021-01958-4
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发表时间：
2021-07
期刊：
影响因子：
8
通讯作者：
Fumi Seto-Tetsuo;M. Arioka;K. Miura;Takeru Inoue;Kazunobu Igawa;K. Tomooka;F. Takahashi-Yanaga;T. Sasaguri
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作者：
Fumi Seto-Tetsuo;M. Arioka;K. Miura;Takeru Inoue;Kazunobu Igawa;K. Tomooka;F. Takahashi-Yanaga;T. Sasaguri
我们以前曾报道，分化诱导因子-1（DIF-1），一种在盘基网柄藻中鉴定的化合物，通过灭活p70核糖体蛋白S6激酶（p70 S6 K）抑制MCF-7乳腺癌细胞的生长。因此，我们首先检查了相同的机制是否在其他乳腺癌细胞中起作用，特别是三阴性乳腺癌（TNBC），这是乳腺癌最具侵袭性和难治性的表型。我们还研究了DIF-1抑制p70 S6 K的机制，重点是AMPK-mTORC 1系统。我们发现DIF-1在多种TNBC细胞系中诱导AMPK和Raptor的磷酸化和p70 S6 K的去磷酸化。接下来，我们检查了AMPK介导的p70 S6 K抑制是否导致TNBC细胞增殖和迁移/浸润的抑制。DIF-1通过抑制STAT 3的翻译而显著降低细胞周期蛋白D1的表达水平，并强烈抑制Snail的表达水平，这分别导致生长和运动的抑制。最后，我们研究了DIF-1是否在体内对TNBC发挥抗癌作用。DIF-1的胃内给药抑制了注射到BALB/c小鼠乳腺脂肪垫中的4 T1-Luc细胞的肿瘤生长和自发性肺转移。DIF-1有望通过一种新的机制导致抗癌药物的开发，包括抗TNBC。
We have previously reported that the differentiation-inducing factor-1 (DIF-1), a compound identified inDictyostelium 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 p70S6Kby focusing on the AMPK-mTORC1 system. We found that DIF-1 induces phosphorylation of AMPK and Raptor and dephosphorylation of p70S6Kin multiple TNBC cell lines. Next, we examined whether AMPK-mediated inhibition of p70S6Kleads 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.