Antitumor Activity of Spicatoside A by Modulation of Autophagy and Apoptosis in Human Colorectal Cancer Cells
Antitumor Activity of Spicatoside A by Modulation of Autophagy and Apoptosis in Human Colorectal Cancer Cells
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DOI：
10.1021/acs.jnatprod.6b00006
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发表时间：
2016-04-01
影响因子：
5.1
通讯作者：
Lee, Sang Kook
中科院分区：
文献类型：
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作者：
Kim, Won Kyung;Pyee, Yuna;Lee, Sang Kook
研究了从白桦块根中分离的甾体皂苷穗花苷A（1）在HCT 116人结直肠癌细胞中的抗肿瘤活性及其潜在机制。化合物1在植入HCT 116细胞的裸鼠异种移植模型中诱导自噬和凋亡性细胞死亡并抑制肿瘤生长。1处理24小时，增强了酸性囊泡细胞器在细胞质中的形成，表明诱导自噬的发生。该事件与自噬标志物（包括微管相关蛋白1轻链3（LC 3）-II、p62、beclin 1、溶酶体相关膜蛋白1（LAMP 1）和组织蛋白酶D）的调节相关，通过抑制PI 3 K/Akt/mTOR信号传导途径、调节促分裂原活化蛋白激酶（MAPK）信号传导和增加p53水平。然而，长时间暴露于1导致细胞凋亡，其特征在于亚G1细胞群和膜联蛋白V/碘化丙啶（PI）阳性细胞群的积累。1诱导的细胞凋亡与凋亡蛋白（包括Bcl-2、Bax和Bid）的调节、细胞色素c释放到胞质溶胶中以及裂解的聚ADP-核糖聚合酶（PAR？）的积累有关。进一步的研究表明，半胱天冬酶对beclin 1的切割在1介导的从自噬到凋亡的转换中起着关键作用。总之，这些发现突出了1在调节自噬和凋亡之间的串扰中的重要性，以及1作为治疗人结直肠癌细胞的新候选物的潜在用途。
The antitumor activity of spicatoside A (1), a steroidal saponin isolated from the tuber of Liriope platyphylla, and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. Compound 1 induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with 1 for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1 (LAMP 1), and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase (MAPK) signaling, and increasing p53 levels. However, a prolonged exposure to 1 resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide (PI)-positive cell population. Apoptosis induced by 1 was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly-ADP-ribose polymerase (PAR?). Further study revealed that cleavage of beclin 1 by caspases plays a critical role in the 1-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of 1 in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of 1 as a novel candidate in the treatment of human colorectal cancer cells.