代谢酶PFKFB3对肿瘤化疗敏感性的调控机理研究

化疗是常用的临床肿瘤治疗手段，然而肿瘤细胞对化疗药物的抵抗性是导致疗效不佳的重要原因。肿瘤细胞可通过提高糖酵解水平避免化疗诱导的细胞凋亡，然而其中的相关机制尚未阐明。代谢酶PFKFB3催化生成的F2,6BP是糖酵解通路的强效激活剂，我们的前期工作发现PFKFB3的抑制可增加化疗药物Cisplatin诱导的肿瘤细胞凋亡；此外，该酶的乙酰化水平在Cisplatin处理条件下显著增强。代谢酶的乙酰化修饰是其功能的重要调控方式。我们将在本项目中重点研究PFKFB3的乙酰化修饰对其调控的糖酵解过程的影响及分子机制，以及PFKFB3对肿瘤细胞响应化疗药物作用过程中的功能调控，以期提出可增强化疗药物对肿瘤抑制效果和特异性的新的作用靶点。此外，我们还将对PFKFB3在细胞核内潜在的新功能进行探索，这对于我们更深入地理解PFKFB3参与化疗作用调控的机制，以及更全面地了解PFKFB3的生理功能具有重要意义。

Chemotherapy is a common clinical strategy for cancer treatment. However, the effect of chemotherapy is often compromised by the existence of drug resistance of cancer cell. Cancer cells are able to evade chemotherapy induced cell apoptosis through elevating glycolytic level, although the mechanism remains elusive. PFKFB3 is a glycolytic enzyme catalyzing the conversion of fructose 6-bisphosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP), which is a very potent stimulator for glycolysis. Our preliminary study demonstrated that inhibition of PFKFB3 sensitizes cells to Cisplatin induced DNA damage response and apoptosis. In addition, Cisplatin also increased the acetylation level of PFKFB3. Acetylation is an important regulatory mechanism for metabolic enzymes. Based on these initial findings, the current project will focus on the mechanism and physiological functions of PFKFB3 acetylation in cell response to chemotherapy. Our aim is to find effective strategies to promote chemotherapy efficiency in cancer treatment. Moreover, we will also explore the potential roles of PFKFB3 in nuclear events, which will expand our understanding of the importance of this enzyme in metabolic control.