Lambda-Carrageenan Enhances the Effects of Radiation Therapy in Cancer Treatment by Suppressing Cancer Cell Invasion and Metastasis through Racgap1 Inhibition
Lambda-Carrageenan Enhances the Effects of Radiation Therapy in Cancer Treatment by Suppressing Cancer Cell Invasion and Metastasis through Racgap1 Inhibition
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DOI：
10.3390/cancers11081192
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发表时间：
2019-08-01
期刊：
影响因子：
5.2
通讯作者：
Nam, Jin-Min
中科院分区：
文献类型：
--
作者：
Wu, Ping-Hsiu;Onodera, Yasuhito;Nam, Jin-Min
放射疗法广泛用于癌症治疗，但放射抗性和放射后存活的癌细胞的转移潜力仍然是关键问题。需要新的治疗方法来改善放射治疗。在这里，我们评估了海藻-卡拉胶（CGN）的治疗效益，以提高放射治疗的疗效，并研究了潜在的分子机制。CGN治疗降低了照射后癌细胞的存活率，并增强了活性氧的积累、细胞凋亡和多倍体形成。此外，CGN抑制3D 1 rECM培养中辐射诱导的化学侵袭和侵袭性生长。我们还使用基因表达微阵列分析筛选靶分子，并集中于Rac GTP酶激活蛋白1（RacGAP 1）。辐射后，RacGAP 1的蛋白表达在几种癌细胞系中上调，CGN治疗显著抑制。RacGAP 1的敲低降低了辐射后的细胞活力和侵袭力。RacGAP 1的过表达部分挽救了CGN的细胞毒性。在小鼠异种移植模型中，与单独治疗相比，局部照射后CGN治疗显著降低了肿瘤生长和肺转移。总之，这些结果表明，CGN可能通过降低癌细胞活力和通过下调RacGAP 1表达抑制辐射诱导的侵袭活性和远端转移来增强放射治疗癌症的有效性。
Radiotherapy is used extensively in cancer treatment, but radioresistance and the metastatic potential of cancer cells that survive radiation remain critical issues. There is a need for novel treatments to improve radiotherapy. Here, we evaluated the therapeutic benefit of lambda-carrageenan (CGN) to enhance the efficacy of radiation treatment and investigated the underlying molecular mechanism. CGN treatment decreased viability in irradiated cancer cells and enhanced reactive oxygen species accumulation, apoptosis, and polyploid formation. Additionally, CGN suppressed radiation-induced chemoinvasion and invasive growth in 3D 1rECM culture. We also screened target molecules using a gene expression microarray analysis and focused on Rac GTPase-activating protein 1 (RacGAP1). Protein expression of RacGAP1 was upregulated in several cancer cell lines after radiation, which was significantly suppressed by CGN treatment. Knockdown of RacGAP1 decreased cell viability and invasiveness after radiation. Overexpression of RacGAP1 partially rescued CGN cytotoxicity. In a mouse xenograft model, local irradiation followed by CGN treatment significantly decreased tumor growth and lung metastasis compared to either treatment alone. Taken together, these results suggest that CGN may enhance the effectiveness of radiation in cancer therapy by decreasing cancer cell viability and suppressing both radiation-induced invasive activity and distal metastasis through downregulating RacGAP1 expression.