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天然化合物 neobractatin 通过上调 RNA 结合蛋白 MBNL2 抑制肿瘤转移。

The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2.

机构信息

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, P.R. China.

Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, 201203, Shanghai, P.R. China.

出版信息

Cell Death Dis. 2019 Jul 18;10(8):554. doi: 10.1038/s41419-019-1789-5.

DOI:10.1038/s41419-019-1789-5
PMID:31320607
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6639345/
Abstract

Tumor metastasis is the predominant cause of lethality in cancer. We found that Neobractatin (NBT), a natural compound isolated from Garcinia bracteata, could efficiently inhibit breast and lung cancer cells metastasis. However, the mechanisms of NBT inhibiting cancer metastasis remain unclear. Based on the RNA-sequencing result and transcriptome analysis, Muscleblind-like 2 (MBNL2) was found to be significantly upregulated in the cells treated with NBT. The Cancer Genome Atlas (TCGA) database analysis indicated that the expression of MBNL2 in breast and lung carcinoma tumor tissues was significantly lower compared to normal tissues. We thus conducted to investigate the antimetastatic role of MBNL2. MBNL2 overexpression mimicked the effect of NBT on breast cancer and lung cancer cell motility and metastasis, in addition significantly enhanced the inhibition effect of NBT. MBNL2 knockdown furthermore partially eliminated the inhibitory effect of NBT on metastasis. Mechanistically, we demonstrated that NBT- and MBNL2-mediated antimetastasis regulation significantly correlated with the pAKT/epithelial-mesenchymal transition (EMT) pathway. Subsequent in vivo study showed the same metastasis inhibition effect in NBT and MBNL2 in MDA-MB-231 xenografts mouse model. This study suggest that NBT possesses significant antitumor activity in breast and lung cancer cells that is partly mediated through the MBNL2 expression and enhancement in metastasis via the pAKT/EMT signaling pathway.

摘要

肿瘤转移是癌症致死的主要原因。我们发现，从藤黄科植物苞芽藤中分离得到的天然化合物 Neobractatin（NBT）能够有效抑制乳腺癌和肺癌细胞的转移。然而，NBT 抑制癌症转移的机制尚不清楚。基于 RNA-seq 结果和转录组分析，发现 NBT 处理的细胞中肌肉盲样蛋白 2（MBNL2）显著上调。癌症基因组图谱（TCGA）数据库分析表明，MBNL2 在乳腺癌和肺癌肿瘤组织中的表达明显低于正常组织。因此，我们进行了研究以探究 MBNL2 的抗转移作用。MBNL2 的过表达模拟了 NBT 对乳腺癌和肺癌细胞迁移和转移的作用，此外还显著增强了 NBT 的抑制作用。MBNL2 的敲低进一步部分消除了 NBT 对转移的抑制作用。在机制上，我们证明了 NBT 和 MBNL2 介导的抗转移调节与 pAKT/上皮间质转化（EMT）通路显著相关。随后的体内研究显示，NBT 和 MBNL2 在 MDA-MB-231 异种移植小鼠模型中具有相同的抑制转移作用。这项研究表明，NBT 对乳腺癌和肺癌细胞具有显著的抗肿瘤活性，部分是通过 MBNL2 的表达和增强 pAKT/EMT 信号通路来抑制转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/5bccf8a52861/41419_2019_1789_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/a24f8233d386/41419_2019_1789_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/0ed65bee5db9/41419_2019_1789_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/5bccf8a52861/41419_2019_1789_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/a24f8233d386/41419_2019_1789_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/87a4bde886f7/41419_2019_1789_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/25cb4073f013/41419_2019_1789_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/265a922c4e3c/41419_2019_1789_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/1cc662c8684a/41419_2019_1789_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/0ed65bee5db9/41419_2019_1789_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6e19/6639345/5bccf8a52861/41419_2019_1789_Fig7_HTML.jpg

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