Fangchinoline exerts anticancer effects on colorectal cancer by inducing autophagy via regulation of the AMPK/mTOR/ULK1 pathway
Fangchinoline exerts anticancer effects on colorectal cancer by inducing autophagy via regulation of the AMPK/mTOR/ULK1 pathway
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Fangchinoline 通过调节 AMPK/mTOR/ULK1 通路诱导自噬对结直肠癌发挥抗癌作用
DOI：
10.1016/j.bcp.2021.114475
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发表时间：
2021
影响因子：
5.8
通讯作者：
Gang Feng
中科院分区：
文献类型：
--
作者：
Xiaocong Xiang;Yunhong Tian;Jiani Hu;Rong Xiong;Matthew Bautista;Li Deng;Qiuju Yue;Yuqi Li;Wei Kuang;Junfeng Li;Kang Liu;Chunlei Yu;Gang Feng
自噬已成为肿瘤治疗的一个有前途的靶点。Fangchinoline（Fan）已被证明在某些类型的癌症中发挥抗癌作用。然而，其对结直肠癌（CRC）的抗癌作用及其机制尚未阐明。更具体地说，Fan对CRC中自噬的调节以前从未报道过。在本研究中，发现Fan在CRC细胞系HT 29和HCT 116中诱导凋亡和自噬通量，这通过LC 3-II蛋白和p62降解的增强水平以及LC 3-II的自噬体和斑点形成的增加来反映。同时，与早期自噬抑制剂3-甲基腺嘌呤（3-MA）联用而与晚期自噬抑制剂氯喹（CQ）联用，进一步增加Fan诱导的细胞死亡，提示Fan诱导的HT 29和HCT 116细胞自噬具有细胞保护作用。此外，Fan处理显示AMPK磷酸化的剂量和时间依赖性增加以及哺乳动物雷帕霉素靶蛋白（mTOR）和ULK 1磷酸化的减少，导致AMPK/mTOR/ULK 1信号通路的激活。此外，在HT 29异种移植模型中，Fan抑制体内肿瘤生长。这些结果表明，Fan在体外和体内均能抑制结直肠癌细胞的生长，揭示了Fan抗结直肠癌作用的新的分子机制，提示Fan是一种有效的自噬诱导剂，有可能成为一种有前途的抗癌药物。
Autophagy has become a promising target for cancer therapy. Fangchinoline (Fan) has been shown to exert anticancer effects in some types of cancers. However, the anticancer effects on colorectal cancer (CRC) and the underlying mechanisms have never been elucidated. More specifically, regulation of autophagy in CRC by Fan has never been reported before. In the present study, Fan was found to induce apoptosis and autophagic flux in the CRC cell lines HT29 and HCT116, which was reflected by the enhanced levels of LC3-II protein and p62 degradation, and the increased formation of autophagosomes and puncta formation by LC3-II. Meanwhile, combination with the early-stage autophagy inhibitor 3-methyladenine (3-MA) but not the late-stage autophagy inhibitor chloroquine (CQ) further increased Fan-induced cell death, which suggested the cytoprotective function of autophagy induced by Fan in both HT29 and HCT116 cells. Moreover, Fan treatment demonstrated a dose- and time-dependently increase in the phosphorylation of AMPK and decrease in the phosphorylation of mammalian target of rapamycin (mTOR) and ULK1, leading to the activation of the AMPK/mTOR/ULK1 signaling pathway. Furthermore, in the HT29 xenograft model, Fan inhibited tumor growthin vivo. These results indicate that Fan inhibited CRC cell growth bothin vitroandin vivoand revealed a new molecular mechanism involved in the anticancer effect of Fan on CRC, suggesting that Fan is a potent autophagy inducer and might be a promising anticancer agent.