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

Juan Zhang,Yuanzhi Lao,Hongxi Xu,Wenwei Fu,Naihan Xu,Li Zhang,Zhili Zhao,Man Wu,Zhaoqing Zheng,Jing Wang

doi:10.1038/s41419-019-1789-5

Juan Zhang, Yuanzhi Lao + Show 8 more

Open Access

https://doi.org/10.1038/s41419-019-1789-5

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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.

Highlights

Breast cancer (BC) and lung cancer (LC) are common lethal malignancies with poor prognoses[1,2], primarily due to metastasis
NBT inhibits the metastasis in MDA-MB-231 and A549 cells Our previous studies have shown that the natural compound NBT, isolated from Garcinia bracteata, exhibited potent antitumor activities[13]; the mechanism of its antitumor action is unclear
These results suggested that NBT suppressed cancer cell metastasis in vitro, possibly through targeting the pAKT/epithelial-mesenchymal transition (EMT) signaling pathways

Summary

Introduction

Breast cancer (BC) and lung cancer (LC) are common lethal malignancies with poor prognoses[1,2], primarily due to metastasis. Cancer metastasis involves local invasion by the primary tumor, followed by circulatory system entry and distant organ infiltration[3,4,5]. The initial step in metastasis is the attainment of invasive capability by the tumor cells. Natural compounds have long been recognized as valuable sources for drug development[6,7,8]. Garcinia species have been studied for more than 70 years, and many bioactive compounds with anticancer potential have been identified[9]. Our previous study demonstrated that the antimetastatic effect of Guttiferone K (GUTK), isolated from Garcinia yunnanensis, resulted from restoration of profilin 1 levels, which are aberrantly reduced in cancer cells[10].

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