Platycodin D抑制β-catenin抑制西妥昔单抗治疗KRAS野生型结直肠癌细胞的转移。

IF 4.2 3区 医学 Q2 ONCOLOGY
Yongming Lv, Wenhong Wang, Yanfei Liu, Ben Yi, Tianhao Chu, Zhiqiang Feng, Jun Liu, Xuehua Wan, Yijia Wang
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引用次数: 0

摘要

西妥昔单抗是一种表皮生长因子受体(EGFR)抑制剂,广泛用于KRAS野生型结直肠癌(CRC)患者的临床治疗。然而,一些患者仍然不能从治疗中获益,因为西妥昔单抗治疗后经常发生转移和耐药。迫切需要新的辅助治疗来抑制西妥昔单抗治疗的结直肠癌细胞的转移。本研究利用两种KRAS野生型CRC细胞HT29和CaCo2,研究从中药桔梗中分离的三萜皂苷——桔梗素D是否能够抑制西妥昔单抗治疗的CRC的转移。无标记定量蛋白质组学分析显示,桔黄素D而非西妥昔单抗显著抑制两种CRC细胞中β-catenin的表达,提示桔黄素D抵消了西妥昔单抗对细胞粘附的抑制作用,起到抑制细胞迁移和侵袭的作用。Western blot结果显示,与单药西妥昔单抗相比,单药或联合用药对Wnt/β-catenin信号通路关键基因β-catenin、c-Myc、Cyclin D1和MMP-7表达的抑制作用增强。擦伤愈合和transwell实验表明,桔黄素D联合西妥昔单抗分别抑制CRC细胞的迁移和侵袭。nu/nu裸鼠HT29和cco2肺转移模型一致显示,platycotin D联合西妥昔单抗在体内显著抑制转移。我们的研究结果提供了一种通过添加桔梗素D来抑制西妥昔单抗治疗期间结直肠癌转移的潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Platycodin D represses β-catenin to suppress metastasis of cetuximab-treated KRAS wild-type colorectal cancer cells.

Platycodin D represses β-catenin to suppress metastasis of cetuximab-treated KRAS wild-type colorectal cancer cells.

Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is extensively used for clinical therapy in KRAS wild-type colorectal cancer (CRC) patients. However, some patients still cannot get benefit from the therapy, because metastasis and resistance occur frequently after cetuximab treatment. New adjunctive therapy is urgently needed to suppress metastasis of cetuximab-treated CRC cells. In this study, we used two KRAS wild-type CRC cells, HT29 and CaCo2, to investigate whether platycodin D, a triterpenoid saponin isolated from Chinese medicinal herb Platycodon grandifloras, is able to suppress the metastasis of cetuximab-treated CRC. Label-free quantitative proteomics analyses showed that platycodin D but not cetuximab significantly inhibited expression of β-catenin in both CRC cells, and suggested that platycodin D counteracted the inhibition effect of cetuximab on cell adherence and functioned in repressing cell migration and invasion. Western blot results showed that single platycodin D treatment or combined platycodin D and cetuximab enhanced inhibition effects on expressions of key genes in Wnt/β-catenin signaling pathway, including β-catenin, c-Myc, Cyclin D1 and MMP-7, compared to single cetuximab treatment. Scratch wound-healing and transwell assays showed that platycodin D combined with cetuximab suppressed migration and invasion of CRC cells, respectively. Pulmonary metastasis model of HT29 and CaCo2 in nu/nu nude mice consistently showed that combined treatment using platycodin D and cetuximab inhibited metastasis significantly in vivo. Our findings provide a potential strategy to inhibit CRC metastasis during cetuximab therapy by addition of platycodin D.

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来源期刊
CiteScore
7.80
自引率
5.00%
发文量
55
审稿时长
12 months
期刊介绍: The Journal''s scope encompasses all aspects of metastasis research, whether laboratory-based, experimental or clinical and therapeutic. It covers such areas as molecular biology, pharmacology, tumor biology, and clinical cancer treatment (with all its subdivisions of surgery, chemotherapy and radio-therapy as well as pathology and epidemiology) insofar as these disciplines are concerned with the Journal''s core subject of metastasis formation, prevention and treatment.
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