Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University , 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea.
J Nat Prod. 2014 May 23;77(5):1135-9. doi: 10.1021/np401078g. Epub 2014 May 14.
The invasive behavior of cancer cells resulting in metastasis is the major cause of cancer-related deaths. Rhapontigenin (1) has various biological activities including anticancer activities. However, whether and how 1 affects cancer invasion has never been explored. Here, we examined the anti-invasive effects of 1 and its underlying molecular mechanisms in the highly invasive human breast cancer cell line designated MDA-MB-231. At noncytotoxic concentrations, 1 strongly suppressed serum-induced cell migration and invasion as judged by Boyden chamber analysis and wound-healing assays, respectively. Compound 1 strikingly reduced Rac1 activity as judged by both absorbance-based and pull-down assays. In addition, its downstream effectors such as WASP-family verprolin homologous proteins 2 (WAVE-2) and p21-activated kinase 1 (PAK1) signaling cascades were attenuated after treatment with 1. Immunofluorescence staining showed that 1 diminished lamellipodia formation at the leading edge of cells. Finally, 1 decreased the phosphorylation of phosphoinisitide-3-kinase (PI3K) and AKT. Rac1 activity was inhibited by the PI3K inhibitor wortmannin. Taken together, these results suggest that 1 suppresses breast cancer cell migration and invasion, which is involved in inhibiting the PI3K-dependent Rac1 signaling pathway.
癌细胞的侵袭行为导致转移是癌症相关死亡的主要原因。瑞普藤宁（1）具有多种生物活性，包括抗癌活性。然而，1 是否以及如何影响癌症侵袭从未被探索过。在这里，我们研究了 1 在高度侵袭性的人乳腺癌细胞系 MDA-MB-231 中的抗侵袭作用及其潜在的分子机制。在非细胞毒性浓度下，1 通过 Boyden 室分析和划痕愈合试验分别强烈抑制血清诱导的细胞迁移和侵袭。基于吸光度的和下拉测定均表明，化合物 1 显著降低 Rac1 活性。此外，在用 1 处理后，其下游效应物如 Wiskott-Aldrich 综合征蛋白家族 verprolin 同源蛋白 2（WAVE-2）和 p21 激活激酶 1（PAK1）信号级联被减弱。免疫荧光染色显示，1 减少了细胞前缘的片状伪足形成。最后，1 降低了磷酸肌醇-3-激酶（PI3K）和 AKT 的磷酸化。Rac1 活性被 PI3K 抑制剂wortmannin 抑制。综上所述，这些结果表明，1 抑制乳腺癌细胞迁移和侵袭，这涉及抑制 PI3K 依赖性 Rac1 信号通路。
