Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation.
Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation.
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DOI：
10.1089/ars.2014.6128
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发表时间：
2016-05-20
影响因子：
6.6
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Pan Y;Lin S;Xing R;Zhu M;Lin B;Cui J;Li W;Gao J;Shen L;Zhao Y;Guo M;Wang JM;Huang J;Lu Y
目的：金属硫蛋白2A（MT 2A）和核因子-κ B（NF-κB）均参与肿瘤的发生和肿瘤的化疗敏感性。我们先前发现MT 2A和IκB-α在人胃癌（GC）中的表达降低与GC患者的不良预后相关。本研究探讨了大蒜衍生物二烯丙基三硫（DATS）和多西他赛（DOC）对胃癌细胞中MT 2A与NF-κB相关性的调节作用。结果如下：DATS可抑制胃癌细胞NF-κB信号通路，导致胃癌细胞G2/M期阻滞和凋亡，最终抑制胃癌细胞增殖和裸鼠成瘤。DATS的抗GC作用是由于其表观遗传学上调MT 2A的能力，MT 2A反过来又增强IκB-α的转录，从而抑制NF-κB在GC细胞中的活化。DATS与DOC联合应用具有协同抗GC活性，并伴有MT 2A上调和NF-κB失活。组织病理学分析显示，DOC治疗后，MT 2A表达显著增加。肿瘤标本中MT 2A高表达的GC患者与肿瘤中MT 2A低表达的患者相比，对化疗的反应显着改善，生存期延长。创新与结论：结论：DATS通过表观遗传上调MT 2A，减弱NF-κB信号通路，发挥其抗GC活性，增强GC对DOC的化疗敏感性。我们的研究结果描绘了MT 2A/NF-κB信号传导对DATS和DOC介导的抗GC作用的机制基础，表明MT 2A可能是接受DOC为基础的治疗的GC患者的化疗敏感性指标，并且是通过DATS和DOC的组合更有效地治疗GC的有希望的靶点。抗氧化剂。氧化还原信号。24，839-854。
Aims: Metallothionein 2A (MT2A) and nuclear factor-kappaB (NF-κB) are both involved in carcinogenesis and cancer chemosensitivity. We previously showed decreased expression of MT2A and IκB-α in human gastric cancer (GC) associated with poor prognosis of GC patients. The present study investigated the effect of diallyl trisulfide (DATS), a garlic-derived compound, and docetaxel (DOC) on regulation of MT2A in relation to NF-κB in GC cells. Results: DATS attenuated NF-κB signaling in GC cells, resulting in G2/M cell cycle arrest and apoptosis, culminating in the inhibition of cell proliferation and tumorigenesis in nude mice. The anti-GC effect of DATS was attributable to its capacity to epigenetically upregulate MT2A, which in turn enhanced transcription of IκB-α to suppress NF-κB activation in GC cells. The combination of DATS with DOC exhibited a synergistic anti-GC activity accompanied by MT2A upregulation and NF-κB inactivation. Histopathologic analysis of GC specimens from patients showed a significant increase in MT2A expression following DOC treatment. GC patients with high MT2A expression in tumor specimens showed significantly improved response to chemotherapy and prolonged survival compared with those with low MT2A expression in tumors. Innovation and Conclusion: We conclude that DATS exerts its anti-GC activity and enhances chemosensitivity of GC to DOC by epigenetic upregulation of MT2A to attenuate NF-κB signaling. Our findings delineate a mechanistic basis of MT2A/NF-κB signaling for DATS- and DOC-mediated anti-GC effects, suggesting that MT2A may be a chemosensitivity indicator in GC patients receiving DOC-based treatment and a promising target for more effective treatment of GC by combination of DATS and DOC. Antioxid. Redox Signal. 24, 839–854.