结肠癌,第三常见的癌症,死亡率高,预后极差。人参皂苷,中草药人参的活性成分,在各种癌症中发挥抗肿瘤作用,包括结肠癌.然而,人参皂苷抑制肿瘤的详细分子机制尚未完全阐明。这里,我们选择了具有代表性的人参皂苷Rg3,并首次报道了Rg3在人结肠癌细胞中诱导线粒体自噬,负责其抗癌作用。Rg3处理导致线粒体损伤和线粒体吞噬体的形成;当自噬被抑制时,受损线粒体的清除可以逆转。接下来,我们的结果表明,Rg3处理激活了PINK1-Parkin信号通路,并将Parkin和泛素蛋白募集到线粒体以诱导线粒体自噬.对Parkin靶标的GO分析显示Parkin与大量线粒体蛋白相互作用,调节线粒体的分子功能。细胞能量代谢酶GAPDH被验证为Parkin的新型底物,被帕金泛素化。此外,GAPDH参与Rg3诱导的线粒体自噬并调节Parkin向线粒体的易位。功能上,Rg3通过调节GAPDH的非溶瘤活性发挥抑制作用,这可能与细胞氧化应激有关。因此,我们的结果表明,帕金的GAPDH泛素化是线粒体自噬诱导的重要机制,有助于人参皂苷的肿瘤抑制功能,这可能是一种新的结肠癌治疗策略。
Colon cancer, the third most frequent occurred cancer, has high mortality and extremely poor prognosis. Ginsenoside, the active components of traditional Chinese herbal medicine Panax ginseng, exerts antitumor effect in various cancers, including colon cancer. However, the detailed molecular mechanism of Ginsenoside in the tumor suppression have not been fully elucidated. Here, we chose the representative ginsenoside Rg3 and reported for the first time that Rg3 induces mitophagy in human colon cancer cells, which is responsible for its anticancer effect. Rg3 treatment leads to mitochondria damage and the formation of mitophagosome; when autophagy is inhibited, the clearance of damaged mitochondria can be reversed. Next, our results showed that Rg3 treatment activates the PINK1-Parkin signaling pathway and recruits Parkin and ubiquitin proteins to mitochondria to induce mitophagy. GO analysis of Parkin targets showed that Parkin interacts with a large number of mitochondrial proteins and regulates the molecular function of mitochondria. The cellular energy metabolism enzyme GAPDH is validated as a novel substrate of Parkin, which is ubiquitinated by Parkin. Moreover, GAPDH participates in the Rg3-induced mitophagy and regulates the translocation of Parkin to mitochondria. Functionally, Rg3 exerts the inhibitory effect through regulating the nonglycolytic activity of GAPDH, which could be associated with the cellular oxidative stress. Thus, our results revealed GAPDH ubiquitination by Parkin as a crucial mechanism for mitophagy induction that contributes to the tumor-suppressive function of ginsenoside, which could be a novel treatment strategy for colon cancer.