Yuping Liu1,2,3, Yang Zhao1,3, Zhonghong Wei1,3, Li Tao1,3, Xiaobo Sheng1,3, Siliang Wang1,3, Jiao Chen2,4, Junshan Ruan1,3, Zhaoguo Liu1,3, Yuzhu Cao1,3, Yunlong Shan1,3, Aiyun Wang1,3, Wenxing Chen1,3, Yin Lu5,6. 1. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China. 2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. 3. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China. 4. Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China. 5. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Chinaprofyinlu@163.com. 6. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Chinaprofyinlu@163.com.
Abstract
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.
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 cancerpatients 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.
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