DT-13基于NMIIA—EGFR/C2GnT-M—HKII联合TPT调节肿瘤有氧糖酵解抗胃癌作用机制研究

有氧糖酵解是肿瘤能量代谢的主要特点，调节异常能量代谢是治疗肿瘤的新方向。拓扑替康（TPT）具有一定毒副作用，临床应用受限。DT-13为短葶山麦冬中分离得到的单体皂苷，申请者前期工作表明DT-13通过NMIIA-EGFR途径增强TPT促胃癌细胞凋亡；体内代谢组学研究发现DT-13可通过抑制有氧糖酵解，协同TPT发挥抗胃癌作用。本课题拟从分子、细胞、整体动物水平，深入研究DT-13联合TPT通过EGFR依赖型NMIIA-EGFR-HKII轴及EGFR非依赖型NMIIA-C2GnT-M-HKII轴抗胃癌有氧糖酵解作用机制；从有氧糖酵解入手，以NMIIA为研究对象，探讨NMIIA 各功能区域对HKII糖基化的作用；探讨DT-13对NMIIA的Motor、Neck、Coiled-coil rod和NHT 4个功能区域的作用；为解决TPT临床毒副作用提供新思路；对DT-13的研究开发具有十分重要的意义

Aerobic glycolysis is the main characteristic of energy metabolism for tumor. Therefore, regulation of aberrant energy metabolism is a novel strategy for cancer treatment. In consideration of TPT suffered restriction because of the serious toxicity, DT-13 which is derived from Liriope muscari (Decne.) Baily showed the synergistic effect with TPT by the apoptosis induction of gastric cancers via Non muscle myosin IIA/Epithelial growth factor receptor pathway. Furthermore, the metabonomics suggested that DT-13 also could regulate aerobic glycolysis to enhance the anticancer effect of TPT. Thus, this study plans to explore the mechanism of the drug combination by EGFR-dependent NMIIA-EGFR-HKII axis and EGFR-independent NMIIA-C2GnT-M-HKII axis, in molecular level, cellular level and animal level. On the one hand, we want to investigate the effect of 4 functional domains of NMIIA on glycosylation of HKII. On the other hand, we prepare to understand the 4 functional domains of NMIIA affected by DT-13. In brief, our study will provide a novel strategy to resolve the toxicity of TPT and promote the drug development of DT-13.