Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan, R.O.C.
Department of Radiation Oncology, Zhongxing Branch, Taipei City Hospital, Taipei, Taiwan.
PLoS One. 2018 Oct 25;13(10):e0205666. doi: 10.1371/journal.pone.0205666. eCollection 2018.
Activation of Ras oncogene in human tumors is associated with radiation-associated metastatic potential. Although ionizing radiation is one important method of cancer treatments, it has been shown to enhance matrix metalloproteinases (MMPs) activity and facilitates a more aggressive cancer phenotype. Our previous studies showed that andrographolide with lower dose rates of radiation could inhibit RAS-transformed cancer metastasis in vivo; however, the molecular mechanisms are not yet clear. In this study, we aimed to explore the anti-metastatic effect of andrographolide combined with radiation on Ras-transformed cells.
RAS-transformed cells were treated with andrographolide in the presence or absence of irradiation (2-4 Gy) or angiotensin II to examine cell invasion. In vivo tumorigenesis assays were also performed. The MMP-2 activity was detected by using Gelatin zymography. Signal transduction of NF-κB subunit, p65 and phosphor-ERK 1/2, were examined by using Western blotting analysis.
Treatment with andrographolide inhibited migration of Ras-transformed cells. Andrographolide treatment with radiation significantly inhibited cancer metastasis in vivo. We found that andrographolide exhibited anti-migration and anti-invasive ability against cancer metastasis via inhibition of MMP2 activity rather than affected MMP-9 and EMT. In addition, combined andrographolide with radiation appeared to be more effective in reducing MMP-2 expression, and this effect was accompanied by suppression of ERK activation that inhibits cancer cell migration and invasion.
These findings suggest that andrographolide enhances the anti-metastatic effect of radiation in Ras-transformed cells via suppression of ERK-mediated MMP-2 activity.
人类肿瘤中 Ras 癌基因的激活与辐射相关的转移潜能有关。虽然电离辐射是癌症治疗的一种重要方法，但它已被证明可以增强基质金属蛋白酶（MMPs）的活性，并促进更具侵袭性的癌症表型。我们之前的研究表明，低剂量率的辐射与穿心莲内酯联合使用可以抑制体内 Ras 转化的癌症转移；然而，其分子机制尚不清楚。在这项研究中，我们旨在探讨穿心莲内酯联合辐射对 Ras 转化细胞的抗转移作用。
用穿心莲内酯处理 Ras 转化细胞，同时存在或不存在辐照（2-4 Gy）或血管紧张素 II 以检测细胞侵袭。还进行了体内肿瘤发生实验。通过明胶酶谱法检测 MMP-2 活性。通过 Western 印迹分析检测 NF-κB 亚基、p65 和 phosphor-ERK 1/2 的信号转导。
穿心莲内酯处理抑制了 Ras 转化细胞的迁移。与辐射联合使用穿心莲内酯显著抑制了体内癌症转移。我们发现，穿心莲内酯通过抑制 MMP2 活性表现出抗迁移和抗侵袭能力，而不是影响 MMP-9 和 EMT。此外，与辐射联合使用穿心莲内酯似乎更有效地降低 MMP-2 表达，这种作用伴随着 ERK 激活的抑制，从而抑制癌细胞的迁移和侵袭。
这些发现表明，穿心莲内酯通过抑制 ERK 介导的 MMP-2 活性增强了辐射对 Ras 转化细胞的抗转移作用。
