脂代谢产物n-3多不饱合脂肪酸通过IAP信号途径调控细胞调亡的实验研究

n-3 polyunsaturated fatty acid (n-3 PUFA) from the lipid metabolism exerts anti-inflammatory and anti-angiogenesis effects in vivo. It is implied that n-3 PUFA also participates in the regulation of apoptosis. Our previous data showed n-3 PUFA enhanced apoptosis in tumor cells but not normal cells. The mechanisms remains unknown. Inhibitor of Apoptosis (IAP) family constitutes a panel of members capable of inhibiting caspases and reducing apoptosis thereby. It remains largely unkown if there is any relationship of IAP with the action of n-3 PUFA. It is well known that tumor habors altered metabolism compared with normal counterpart and serves a good model for exploration of metabolic mechanisms. In the study, we are to use n-3 PUFA to treat tumor cells and explore the effects of n-3 PUFA on the IAP signaling. This study helps to dissect the cross-talk between metabolism and apoptosis, both of which are key biological charateristics for mammalian cells. Also the present study is benefit to facilitate the convergence of metabolism and other signal pathways, and provides new ideas on the interdisciplinary co-operation between metabolism and other subjects.

脂代谢产物n-3多不饱和脂肪酸，在人体内发挥抑制炎症和细胞增殖并抗血管生成的作用。n-3 PUFA还涉及细胞凋亡的调控。课题组前期结果发现n-3PUFA促进凋亡的效应可能仅限于肿瘤细胞而非正常细胞。n-3 PUFA调控细胞凋亡的机制仍不明确。IAP家族是细胞内caspase抑制物，是凋亡调控的重要分子。n-3 PUFA与IAP信号途径的相互作用存在很大空白。肿瘤细胞不同于正常细胞，其代谢调控机制已经发生改变，这提供了一个好的病理条件下异常代谢途径的模型，为全面揭示细胞内代谢途径开辟了新的研究领域。本课题以n-3PUFA为研究对象，利用其可促进肿瘤细胞凋亡的特性，探索对细胞内IAP信号途径的作用及机制，着眼于细胞代谢与细胞调亡两个基本特性的交叉与交谈(cross talk)。本研究将有助于拓宽细胞代谢研究领域，促进代谢通路与其他信号通路的融汇，也为内分泌代谢学科与其他学科交叉融合提供新思路。

肿瘤可能也属于一种代谢性疾病，利用代谢障碍的理论和观点研究肿瘤，为肿瘤的诊断和治疗提供了新的思路。本课题设想，n-3 PUFA可能通过抑制细胞内mTOR信号途径的活化而下调IAP家族成员的表达，进而促进细胞凋亡。.本研究发现不同肺癌细胞株对n-3 PUFA敏感性差异极大。肺腺癌H460及大细胞癌H1975对n-3 PUFA相当敏感，而H1299则极不敏感。进而发现n-3 PUFA不同成份DHA 及EPA对肿瘤生长有明显抑制作用，呈剂量时间依赖性。其毒性主要通过诱导细胞凋亡发生，而对细胞周期影响较少。进一步发现，其诱导凋亡主要通过改变细胞内survivin表达发挥作用。本研究为肺癌的治疗作出了新的探索，可望为肺癌的辅助治疗有所帮助。