雄黄有效成分硫化砷通过调控NFATc3-RAG1-DSB杀伤胃癌细胞的机制

胃癌是我国高发的恶性肿瘤，晚期胃癌因缺乏有效药物治疗而预后极差。近年来发现传统中药雄黄具有抗癌潜力，但其作用机制尚不明确。本课题组首次报道了雄黄有效成分硫化砷的抗胃癌作用，发现硫化砷可抑制胃癌细胞的增殖和侵袭转移，而NFATc3是其作用的靶分子。进一步研究发现，硫化砷可引起癌细胞内RAG1上调从而导致DNA双链损伤（DSB）；干扰NFATc3后也出现此变化。据此，我们认为：硫化砷可能通过调控NFATc3-RAG1-DSB杀伤胃癌细胞从而抑制肿瘤。本课题拟从分子、细胞、动物和患者水平多维度深入研究硫化砷下调NFATc3的机制、RAG1的生物学作用及NFATc3对RAG1的调控机制，最终明确NFATc3-RAG1-DSB途径在硫化砷治疗胃癌过程中的作用及其细胞分子机制。本研究是应用现代科技手段对传统中药抗肿瘤药理的深入挖掘，将为扩大雄黄治疗胃癌的新适应症提供确切的科学依据和强有力的理论支持。

Gastric cancer is a common malignant disease in China with poor survival and very few effective treatments. Realgar, a traditional Chinese medicine, has been found to exert anticancer effect, but its mechanism remains unclear. . We previously reported that arsenic sulfide, the active component of realgar, inhibited the proliferation, invasion and migration of gastric cancer cells through targeting NFAT pathway. . We have also discovered that arsenic sulfide stimulates the expression of RAG1 which led to DNA double strand damage (DSB) in gastric cancer cells. Knockdown of NFATc3 resulted in similar DNA damage response with increased RAG1. . Thus, we hypothesize that arsenic sulfide upregulates RAG1 and stimulates DSB in gastric cancer cells by inhibiting NFATc3.. This proposal aims to further investigate the regulatory mechanism of NFATc3-RAG1-DSB pathway utilized by arsenic sulfide using cell lines, animals and patient samples.. This is a novel mechanism that can be further delineated to understand the cytotoxic mechanism of arsenic sulfide and provide a new platform for further understanding the hidden mystery on the many aspects of anti-cancer efficacy of this traditional Chinese medicine.