GFPT1是己糖胺合成途径的限速酶。GFPT1在肿瘤中高表达并与临床不良预后密切相关,但关于其在肿瘤中的详细生物学功能及机制研究尚不明确。我们前期研究发现GFPT1在前列腺癌细胞中高表达,抑制GFPT1导致肿瘤细胞增殖能力下降,而且用AMPK激活剂处理的情况下,与对照组细胞相比敲低GFPT1表达肿瘤细胞中AMPK磷酸化水平上调更加明显。AMPK是调控肿瘤代谢关键分子,关于GFPT1调控AMPK磷酸化的机制还未见报道。在此基础上,本项目拟研究GFPT1在肿瘤中的生物学功能,同时探讨GFPT1调控AMPK磷酸化的机制,结合代谢组学分析GFPT1差异表达引起的代谢物变化,筛选出与AMPK相关差异代谢物及关键基因,并验证筛选出的代谢通路对GFPT1调控肿瘤致瘤性的影响,阐明GFPT1通过AMPK调控肿瘤代谢的机制。并通过裸鼠模型及临床数据分析验证该机制,为临床肿瘤治疗提供新的理论依据。

L-Glutamine: D-fructose-6-phosphate (F6P) 1 aminotransferase (GFPT1) is the first and rate limiting enzyme in the hexosamine biosynthetic pathway. GFPT1 is highly expressed in tumor, which is closely associated with clinical poor prognosis, however, the mechanism and function in tumor of GFPT1 is incompletely understood. Our previous study demonstrated that GFPT1 was significantly upregulated in prostate cancer cells. Consistent with this, cell proliferation was markedly postponed in GFPT1-suppressed human prostate cancer (DU145) cells. Moreover, following the treatment with 2-deoxyglucose (2-DG), the AMPK activity was elevated more obviously in GFPT1-Knockdown cells compare with the control cells. Although AMPK is a critical regulator in energy and nutrient metabolism, the mechanism of GFPT1 regulates AMPK phosphorylation has not been described yet. Based on these results, this project will focus on the potential function of GFPT1 in tumor progression and the regulatory mechanism of GFPT1 on AMPK phosphorylation. Furthermore, the novel chromatography–mass spectrometry method will be applied to study the differential metabolites of the cellular metabolism between the control cells and GFPT1 abnormal-expressed cells. And the metabolism and metabolic protein related to the AMPK pathway will be analyzed. In addition, the potential effect of these key metabolic pathways on GFPT1 regulation of tumor malignant behaviors will be investigated. Eventually, we will define the GFPT1 regulation mechanisms in cancer metabolism through regulation AMPK. Furthermore the mechanism will be validated in the nude mice model and clinical data .Collectively, our study will provide a novel insight for the therapy of cancer.