Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway.,Acta Pharmacologica Sinica

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Tubeimoside-1, a triterpenoid saponin, induces cytoprotective autophagy in human breast cancer cells in vitro via Akt-mediated pathway.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-10-12 , DOI: 10.1038/s41401-018-0165-9
Shi-Long Jiang ₁ , Yi-di Guan ₁ , Xi-Sha Chen ₁ , Peng Ge ₁ , Xin-Luan Wang ₂ , Yuan-Zhi Lao ₃ , Song-Shu Xiao ₄ , Yi Zhang ₅ , Jin-Ming Yang ₆ , Xiao-Jun Xu ₇ , Dong-Sheng Cao _{1,

8} , Yan Cheng _{1,

8}

Affiliation

Autophagy, a form of cellular self-digestion by lysosome, is associated with various disease processes including cancers, and modulating autophagy has shown promise in the treatment of various malignancies. A number of natural products display strong antitumor activity, yet their mechanisms of action remain unclear. To gain a better understanding of how traditional Chinese medicine agents exert antitumor effects, we screened 480 natural compounds for their effects on autophagy using a high content screening assay detecting GFP-LC3 puncta in HeLa cells. Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), was identified as a potent activator of autophagy. The activation of autophagy by TBMS1 was evidenced by increased LC3-II amount and GFP-LC3 dots, observation of autophagosomes under electron microscopy, and enhanced autophagic flux. To explore the mechanisms underlying TBMS1-activated autophagy, we performed cheminformatic analyses and surface plasmon resonance (SPR) binding assay that showed a higher likelihood of the binding between Akt protein and TBMS1. In three human breast cancer cell lines, we demonstrated that Akt-mTOR-eEF-2K pathway was involved in TBMS1-induced activation of autophagy, while Akt-mediated downregulations of Mcl-1, Bcl-xl, and Bcl-2 led to the activation of apoptosis of the breast cancer cells. Inhibition of autophagy enhanced the cytotoxic effect of TBMS1 via promoting apoptosis. Our results demonstrate the role and mechanism of TBMS1 in activating autophagy, suggesting that inhibition of cytoprotective autophagy may act as a therapeutic strategy to reinforce the activity of TBMS1 against cancers.

中文翻译：

Tubeimoside-1 是一种三萜皂苷，通过 Akt 介导的途径在体外诱导人乳腺癌细胞中的细胞保护性自噬。

自噬是溶酶体细胞自我消化的一种形式，与包括癌症在内的各种疾病过程有关，调节自噬在治疗各种恶性肿瘤方面显示出前景。许多天然产物显示出很强的抗肿瘤活性，但它们的作用机制尚不清楚。为了更好地了解中药如何发挥抗肿瘤作用，我们使用检测 HeLa 细胞中 GFP-LC3 斑点的高内涵筛选试验筛选了 480 种天然化合物对自噬的影响。Tubeimoside-1 (TBMS1) 是一种从 Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae) 中提取的三萜皂苷，被鉴定为一种有效的自噬激活剂。增加的 LC3-II 量和 GFP-LC3 点证明了 TBMS1 对自噬的激活，在电子显微镜下观察自噬体，并增强自噬通量。为了探索 TBMS1 激活自噬的潜在机制，我们进行了化学信息学分析和表面等离子体共振 (SPR) 结合测定，结果表明 Akt 蛋白与 TBMS1 之间结合的可能性更高。在三种人乳腺癌细胞系中，我们证明 Akt-mTOR-eEF-2K 通路参与了 TBMS1 诱导的自噬激活，而 Akt 介导的 Mcl-1、Bcl-xl 和 Bcl-2 下调导致激活乳腺癌细胞的凋亡。抑制自噬通过促进细胞凋亡增强了 TBMS1 的细胞毒作用。我们的结果证明了 TBMS1 在激活自噬中的作用和机制，

更新日期：2019-01-26

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