Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways
Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways
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小檗碱通过抑制 MAPK/mTOR/p70S6K 和 Akt 信号通路诱导细胞抑制自噬，在体外和体内抑制人胃癌细胞生长
DOI：
10.1016/j.biopha.2020.110245
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发表时间：
2020-08-01
影响因子：
7.5
通讯作者：
Kang, Ning
中科院分区：
文献类型：
--
作者：
Zhang, Qiang;Wang, Xiaobing;Kang, Ning
小檗碱是一种异喹啉类生物碱，具有良好的抗肿瘤作用，是一种潜在的抗肿瘤药物。然而，参与抗胃癌的分子机制仍然知之甚少。在此，首次研究了小檗碱在体外和体内通过诱导细胞抑制性自噬抑制胃癌的作用。结果表明，小檗碱对胃癌BGC-823细胞有明显的生长抑制作用，对人外周血单个核细胞无毒性作用。用小檗碱处理引发细胞自噬，如通过单丹酰尸胺染色和GFP-LC 3的点状分布以及LC 3-II、Beclin-1和p-ULK 1促进和p62降解所证明的。3-MA、CQ、Baf-Al和BECN 1 siRNA抑制自噬后，小檗碱处理的胃癌细胞存活率明显提高，证实了小檗碱诱导自噬的抗癌作用。机制研究表明，小檗碱抑制mTOR，Akt和MAPK（ERK，JNK和p38）通路，从而诱导自噬。抑制上述通路可增加小檗碱诱导的自噬和细胞毒性。有趣的是，mTOR/p70 S6 K被MAPK而不是Akt抑制。此外，抑制自噬逆转小檗碱下调mTOR，Akt和MAPK。在异种移植物中，小檗碱诱导的自噬导致肿瘤增殖的抑制而没有副作用，并且蛋白质印迹显示来自小檗碱处理的小鼠的肿瘤中的p-mTOR、p-p70 S6 K、p-Akt、p-ERK、p-JNK和p-p38的明显减弱。这些结果表明，小檗碱通过抑制MAPK/mTOR/p70 S6 K和Akt诱导细胞自噬抑制人胃癌细胞的生长，为胃癌的治疗提供了分子基础。
Berberine, an isoquinoline alkaloid from Coptidis Rhizoma, has been characterized as a potential anticancer drug due to its good anti-tumor effects. However, the molecular mechanisms involved in anti-gastric cancer remain poorly understood. Herein, the role of berberine in gastric cancer suppression by inducing cytostatic autophagy in vitro and in vivo was first investigated. Results showed that berberine induced an obvious growth inhibitory effect on gastric cancer BGC-823 cells without toxicity to human peripheral blood mononuclear cells. Treatment with berberine triggered cell autophagy, as demonstrated by the punctuate distribution of monodansylcadaverine staining and GFP-LC3, as well as the LC3-II, Beclin-1 and p-ULK1 promotion, and p62 degradation. Inhibition of autophagy by 3-MA, CQ, Baf-Al and BECN1 siRNA obviously increased cell viability of berberine-exposed gastric cancer cells, which confirmed the anti-cancer role of autophagy induced by berberine. Mechanistic studies showed that berberine inhibited mTOR, Akt and MAPK (ERK, JNK and p38) pathways thereby inducing autophagy. Inhibition of above pathways increases berberine induced autophagy and cytotoxicity. Interestingly, mTOR/p70S6K was inhibited by the MAPK but not Akt. Furthermore, inhibition of autophagy reversed berberine down-regulated mTOR, Akt and MAPK. In xenografts, the berberine induced autophagy leads to suppression of tumor proliferation with no side-effect, and western blotting displayed an apparent attenuation of p-mTOR, p-p70S6K, p-Akt, p-ERK, p-JNK and p-p38 in tumors from berberine treated mice. Briefly, these results indicated that berberine repressed human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt, and provided a molecular basis for the treatment of gastric cancer.