基于肿瘤细胞的异常脂代谢探讨千层纸素调控肿瘤细胞增殖及分化的分子机制

靶向调节肿瘤细胞能量代谢，开发具有选择性的抗肿瘤药物，是当前极具潜力的癌症治疗策略之一。除了有氧糖酵解外，脂代谢也是肿瘤细胞中极其重要的一项代谢过程，它为生物膜生成提供原料、产生ATP、并促进肿瘤细胞的生长、耐药及转移。前期研究表明，千层纸素具有较强的抗肿瘤活性，且对正常组织及细胞毒性小，其作用机制与调控肿瘤细胞的异常能量代谢相关，能抑制有氧糖酵解。目前，关于千层纸素调控癌细胞脂代谢的研究，国内外尚未见报道。本项目旨在研究千层纸素对肿瘤细胞脂肪酸代谢的调控机制，通过建立体内高脂饮食条件下的原发性结肠癌动物模型并应用分子生物学技术，重点探讨HIF1α、PPAR、sirtuin三个系统对脂肪酸合成及β氧化的干预机制，找到关键调控因子。在此基础上，进一步研究千层纸素干预下脂肪酸代谢、以及肿瘤相关性脂肪细胞对肿瘤细胞增殖、周期及分化的影响。本项目为千层纸素靶向肿瘤细胞代谢的研究提供了新的思路。

Currently, targeting energy metabolism in cancer cells to develop novel anticancer drugs with selectivity is one of most potential strategies for cancer therapy. In addition to aerobic glycolysis, lipid metabolism is also an extremely important metabolic reactions in cancer cells, which provides raw material for biofilm generation, produces ATP, and promotes cell growth, drug resistance and metastasis. Previous studies show that oroxylin A exhibits strong anti-tumor activity with little toxicity in normal tissues and cells. Oroxylin A can modulate biological energy metabolism of cancer cells and inhibit aerobic glycolysis. At present, the studies involving in the effects of oroxylin A on lipid metabolism in cancer cells have not been reported both at home and abroad. This project is aims to study the regulation of oroxylin A on the fatty acid metabolism in cancer cells. Using primary colon cancer model induced by the high fat diet combined chemical stimulation and other molecular biology technologies, our key point will be focus on the regulating mechanism of oroxylin A targeting the synthesis and β-oxidation of fatty acids through the involvement of HIF1-α, PPAR, and Sirtuin systems. On this basis, we will explore the influences of fatty acid metabolism and tumor-associated adipocytes on cell proliferation, cell cycle and differentiation of cancer cells upon oroxylin A treatment in further studies. This project will provide new insight for the cancer therapies targeting cancer mechanism of oroxylin A.