Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells
Inhibition of Akt signaling and enhanced ERK1/2 activity are involved in induction of macroautophagy by triterpenoid B-group soyasaponins in colon cancer cells
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DOI：
10.1093/carcin/bgi214
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发表时间：
2006-02-01
期刊：
影响因子：
4.7
通讯作者：
Singletary, KW
中科院分区：
文献类型：
--
作者：
Ellington, AA;Berhow, MA;Singletary, KW
已发现三萜B组大豆皂苷在可通过食用豆类食品获得的浓度下诱导人结肠癌细胞中的大自噬。在本研究中，通过测量与自噬相关的信号转导通路的变化来评估大豆皂苷诱导自噬作用的机制。具体而言，Akt信号传导途径的抑制和ERK 1/2活性的增强先前已经涉及控制哺乳动物癌细胞中巨自噬的诱导。在这里，我们表明，这些途径也参与了B组大豆皂甙诱导的macroautophagy，在自噬活性显着增加之前的酶活性的变化。HCT-15细胞的自噬能力在皂苷暴露后6小时显著增加，这使得我们测量在该时间点之前的信号传导事件的改变。我们确定，暴露于B组大豆皂苷抑制Akt活性最大50%，这与Akt-丝氨酸（473）残基的活化磷酸化的减少有关。此外，ERK 1/2活性显著增加了60%，并且被确定为B组大豆皂苷诱导的自噬所必需的。raf-1激酶已被确定为Akt和ERK 1/2信号级联之间的潜在交叉点。B组大豆皂苷处理后，raf-1的活性显著增加，最高达200%，表明该酶部分调节增强的ERK 1/2活性。这些结果提供了新的见解信号事件，控制诱导自噬的B组大豆皂甙在人类结肠癌细胞，并建议大豆皂甙值得进一步研究作为潜在的结肠癌化学预防剂。
Triterpenoid B-group soyasaponins have been found to induce macroautophagy in human colon cancer cells at concentrations obtainable through consumption of legume foodstuffs. In the present studies the mechanism(s) for this autophagy-inducing action of soyasaponins was evaluated by measuring changes in signal transduction pathways associated with autophagy. Specifically, inhibition of the Akt signaling pathway and enhanced activity of ERK1/2 have previously been implicated in controlling induction of macroautophagy in mammalian cancer cells. Here we show that these pathways are also involved in B-group soyasaponin-induced macroautophagy, as changes in enzyme activities preceded significant increases in autophagic activity. The autophagic capacity of HCT-15 cells was significantly increased by 6 h post-saponin exposure, which led us to measure alterations in signaling events that preceded this time point. We determined that exposure to B-group soyasaponins suppressed Akt activity maximally by 50%, which was associated with a reduction in the activating phosphorylation of the Akt-serine(473) residue. In addition, ERK1/2 activity was significantly increased by 60%, and was determined to be necessary for B-group soyasaponin-induced autophagy. The raf-1 kinase has been identified as a potential point of cross-talk between the Akt and ERK1/2 signaling cascades. Following B-group soyasaponin treatment activity of raf-1 was significantly increased by a maximal 200%, suggesting that this enzyme in part modulates the enhanced ERK1/2 activity. These results provide new insights into the signaling events that control induction of autophagy by B-group soyasaponins in human colon cancer cells and suggest that soyasaponins warrant further study as potential colon cancer chemopreventive agents.