用有机硫化合物二烯丙基三硫（DATS）靶向硫氧还蛋白系统可减轻三阴性乳腺癌（TNBC）的进展和转移。
Targeting Thioredoxin System with an Organosulfur Compound, Diallyl Trisulfide (DATS), Attenuates Progression and Metastasis of Triple-Negative Breast Cancer (TNBC).
作者信息
Liu Yuping, Zhao Yang, Wei Zhonghong, Tao Li, Sheng Xiaobo, Wang Siliang, Chen Jiao, Ruan Junshan, Liu Zhaoguo, Cao Yuzhu, Shan Yunlong, Wang Aiyun, Chen Wenxing, Lu Yin
机构信息
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
出版信息
Cell Physiol Biochem. 2018;50(5):1945-1963. doi: 10.1159/000494874. Epub 2018 Nov 5.
BACKGROUND/AIMS: Metastasis is the leading cause resulting in high mortality in triple negative breast cancer (TNBC) patients. Cancer cells are skilled at utilizing thioredoxin (Trx) system as an efficient antioxidant system to counteract oxidative damage, facilitating the occurrence of metastasis. Here, we identified an organosulfur compound named DATS isolated from garlic, that inhibits the expression of Trx-1 and the enzyme activity of Trx reductase in breast cancer cells.
METHODS
Tissue microarray of breast cancer patients and immunohistochemical method were used to analyze the role of Trx-1 in breast cancer metastasis. Spotaneous metastasis model and experimental metastasis model combined with HE staining, immunohistochemistry were used to verify in vivo anti-metastatic effect of DATS as well as its regulation on thioredoxin. Western blot, immunofluorescence, redox state assessment and detection of enzyme activity were employed to determine the effect of DATS on thioredoxin system. Trx-1 siRNA interference was used to investigate the conclusive evidence that Trx-1 was the target of DATS.
RESULTS
In agreement with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of reduced form of Trx-1 was dramatically decreased. Furthermore, in vivo, DATS administration was observed to significantly suppress spontaneous and experimental metastasis in nude mice. Delivery of DATS also resulted in decreased expression of Trx-1 as the direct target, as well as expression of NF-κB and MMP2/9 in primary tumor and lung tissue. Notably, the effects of DATS on the expression of downstream metastasis-associated genes were mediated by Trx-1, as demonstrated by the combination use of DATS and Trx-1 siRNA.
CONCLUSION
Collectively, this present study indicates that targeting Trx system with DATS may provide a promising strategy for treating metastasis of TNBC.
背景/目的：转移是导致三阴性乳腺癌（TNBC）患者高死亡率的主要原因。癌细胞善于利用硫氧还蛋白（Trx）系统作为一种有效的抗氧化系统来对抗氧化损伤，从而促进转移的发生。在此，我们鉴定了一种从大蒜中分离出的有机硫化合物DATS，它能抑制乳腺癌细胞中Trx-1的表达和Trx还原酶的酶活性。
方法
采用乳腺癌患者组织芯片和免疫组化方法分析Trx-1在乳腺癌转移中的作用。利用自发转移模型和实验性转移模型，结合苏木精-伊红染色、免疫组化，验证DATS的体内抗转移作用及其对硫氧还蛋白的调节作用。采用蛋白质免疫印迹法、免疫荧光法、氧化还原状态评估和酶活性检测来确定DATS对硫氧还蛋白系统的影响。利用Trx-1小干扰RNA（siRNA）干扰来研究Trx-1是DATS作用靶点的确凿证据。
结果
与DATS使Trx-1从细胞质向细胞核的转位减少一致，Trx-1还原形式的产生显著降低。此外，在体内，观察到给予DATS可显著抑制裸鼠的自发转移和实验性转移。给予DATS还导致作为直接靶点的Trx-1表达降低，以及原发性肿瘤和肺组织中核因子κB（NF-κB）和基质金属蛋白酶2/9（MMP2/9）的表达降低。值得注意的是，如DATS与Trx-1 siRNA联合使用所示，DATS对下游转移相关基因表达的影响是由Trx-1介导的。
结论
总体而言，本研究表明用DATS靶向Trx系统可能为治疗TNBC转移提供一种有前景的策略。
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