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新型二硫代氨基甲酸盐 DpdtC 通过抑制 HER2-ERK1/2 信号通路使 NDRG1 上调从而抑制过表达 HER2 的癌细胞。

The novel dithiocarbamate, DpdtC suppresses HER2-overexpressed cancer cells by up-regulating NDRG1 via inactivation of HER2-ERK 1/2 signaling.

机构信息

School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.

College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China.

出版信息

Sci Rep. 2018 Feb 21;8(1):3398. doi: 10.1038/s41598-018-21768-1.

DOI:10.1038/s41598-018-21768-1
PMID:29467385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5821706/
Abstract

Dithiocarbamate has been tested for its effective anti-tumor activity, but the underlying mechanism remains unclear. We previously prepared a novel diththiocarbamate derivative, DpdtC with an ability of catalase inhibition. Here, we for the first time investigated the growth inhibition effects of DpdtC on HER2-amplified cancer cells and elucidated its mechanism of action. Results showed that DpdtC exerted the potent anti-tumor effects against HER2-overexpressed SK-OV-3 and SK-BR-3 cells, especially on SK-OV-3 cells with a higher NDRG1 level, which was also confirmed in the SK-OV-3 xenograft model. Interestingly, we observed that NDRG1 was up-regulated, while membrane expression of HER2 was regressed in SK-OV-3 cells upon DpdtC treatment. In agreement, silencing endogenous NDRG1 also increased the expression of HER2 in SK-OV-3 cells, while overexpressing NDRG1 decreased HER2 expression in SK-BR-3 cells. Furthermore, our results showed the formation of the EGFR/HER2 heterodimer was attenuated and phosphorylation of ERK1/2 was inhibited in SK-OV-3 cells when treated with DpdtC. Collectively, these observations demonstrated that NDRG1 plays an important role in mediating the inhibition effects of DpdtC in HER2-overexpressed cancer cells via selective targeting of the HER2-ERK1/2 pathway. Hence, our investigation suggests that up-regulation of NDRG1 by DpdtC is a promising therapeutic approach in HER2-overexpressed cancers.

摘要

二硫代氨基甲酸盐已被测试其有效的抗肿瘤活性，但潜在的机制仍不清楚。我们以前制备了一种新型的二硫代氨基甲酸盐衍生物 DpdtC，具有过氧化氢酶抑制能力。在这里，我们首次研究了 DpdtC 对 HER2 过表达癌细胞的生长抑制作用，并阐明了其作用机制。结果表明，DpdtC 对 HER2 过表达的 SK-OV-3 和 SK-BR-3 细胞具有很强的抗肿瘤作用，特别是对 NDRG1 水平较高的 SK-OV-3 细胞，这在 SK-OV-3 异种移植模型中也得到了证实。有趣的是，我们观察到 DpdtC 处理后 SK-OV-3 细胞中 NDRG1 上调，而 HER2 的膜表达则下调。一致地，沉默内源性 NDRG1 也增加了 SK-OV-3 细胞中 HER2 的表达，而过表达 NDRG1 则降低了 SK-BR-3 细胞中 HER2 的表达。此外，我们的结果表明，DpdtC 处理 SK-OV-3 细胞时，EGFR/HER2 异二聚体的形成减弱，ERK1/2 的磷酸化受到抑制。总之，这些观察结果表明，NDRG1 在介导 DpdtC 在 HER2 过表达癌细胞中的抑制作用中发挥重要作用，通过选择性靶向 HER2-ERK1/2 途径。因此，我们的研究表明，DpdtC 上调 NDRG1 是治疗 HER2 过表达癌症的一种有前途的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/21d1e06b0faf/41598_2018_21768_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/21d1e06b0faf/41598_2018_21768_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/a9a2c77d337a/41598_2018_21768_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/0edd7521a2d3/41598_2018_21768_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/1079cf520bd0/41598_2018_21768_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/c04288459f4c/41598_2018_21768_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/a373ebb4cd3f/41598_2018_21768_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9b1e/5821706/21d1e06b0faf/41598_2018_21768_Fig7_HTML.jpg

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