Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells
Betulin Inhibits Lung Metastasis by Inducing Cell Cycle Arrest, Autophagy, and Apoptosis of Metastatic Colorectal Cancer Cells
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DOI：
10.3390/nu12010066
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发表时间：
2020-01-01
期刊：
影响因子：
5.9
通讯作者：
Hong, Seung-Heon
中科院分区：
文献类型：
--
作者：
Han, Yo-Han;Mun, Jeong-Geon;Hong, Seung-Heon
背景：结直肠癌（CRC）是世界范围内患病率和死亡率较高的疾病之一。特别是，转移性结直肠癌的手术可能性很低，并且缺乏适当的治疗。在本研究中，我们进行了实验来研究桦木醇对转移性结直肠癌的抑制作用及其相关机制。方法：采用水溶性四唑测定法测定桦木醇对转移性结直肠癌细胞活力的影响。进行流式细胞术和TUNEL实验来确认桦木醇是否可以诱导细胞凋亡、自噬和细胞周期停滞。采用肺转移小鼠模型来评估桦木醇的抗转移作用。结果：桦木醇降低了转移性 CRC 细胞的活力，包括 CT26、HCT116 和 SW620 细胞系。通过 PI3K/Akt/mTOR 失活，桦木醇诱导 AMPK 介导的 CT26 和 HCT116 细胞的 G0/G1 期停滞和自噬。此外，桦木醇通过丝裂原激活蛋白激酶信号通路在转移性结直肠癌细胞中发生半胱天冬酶依赖性细胞凋亡。此外，口服桦木醇显着抑制CT26细胞向肺的转移。结论：我们的结果证明了桦木醇在转移性结直肠癌治疗中的抗转移作用和治疗潜力。
Background: Colorectal cancer (CRC) is one of the diseases with high prevalence and mortality worldwide. In particular, metastatic CRC shows low probability of surgery and lacks proper treatment. In this study, we conducted experiments to investigate the inhibitory effect of betulin against metastatic CRC and related mechanisms. Methods: Water-soluble tetrazolium assay was used to determine the effect of betulin on metastatic CRC cell viability. Flow cytometry and TUNEL assay were performed to confirm whether betulin can induce apoptosis, autophagy, and cell cycle arrest. A lung metastasis mouse model was employed to estimate the anti-metastatic effect of betulin. Results: betulin decreased viability of metastatic CRC cells, including CT26, HCT116, and SW620 cell lines. Through PI3K/Akt/mTOR inactivation, betulin induced AMPK-mediated G0/G1 phase arrest and autophagy of CT26 and HCT116 cells. In addition, betulin occurred caspase-dependent apoptosis via the mitogen-activated protein kinase signaling pathway in metastatic CRC cells. Moreover, orally administered betulin significantly inhibited metastasis of CT26 cells to the lung. Conclusion: Our results demonstrate the anti-metastatic effect and therapeutic potential of betulin in metastatic CRC treatment.