磷酸化FOXO1抑制前列腺癌Warburg效应的作用及机制研究

Advanced prostate cancer is not sensitive to existing treatment methods, the progression mechanism is unclear. The theory of Warburg effect promoting tumor growth is one of the latest research hotspots, which understand cancer from the perspective of metabolism. Pyruvate kinase M2 (PKM2) is the key to the occurrence of the Warburg effect, which is regulated by the ERK signal. However, how it starts is unknown..It has been thought that phosphorylated-fork transcription factor O1 (FOXO1) has no biological function. We found that phosphorylated-FOXO1 still has tumor suppress function. Phosphorylated-FOXO1 binds to the scaffold protein IQGAP1, causing IQGAP1 to conformation changes, leading to ERK inactivation, which is a new breakthrough in this field. We also found that FOXO1 always lose in prostate cancer tissues, and higher tumor grade, lower FOXO1 expression. Thus, the loss of FOXO1 leads to an unrestricted activation of the ERK signal, which may be the starting factor for the Warburg effect..The aim of this study is to elucidate the inhibitory effect and mechanism of phosphorylated-FOXO1 and a phosphorylated-FOXO1 liked P2SE peptide on the Warburg effect in prostate cancer at the cellular and animal levels using biochemical and cellular molecular biology methods. This study will improve the regulation and control network of Warburg effect and lay a scientific foundation for the small peptide with independent intellectual property rights converting to clinical practice.

晚期前列腺癌对现有治疗方法均不敏感，演进机制不明。Warburg效应促进肿瘤生长的理论从代谢学角度认识肿瘤，是最新热点。丙酮酸激酶M2是Warburg效应发生的关键，受ERK信号调节，但始动环节不明。.以往认为，叉头转录因子O1（FOXO1）磷酸化后即失去功能。我们发现，磷酸化FOXO1仍具肿瘤抑制作用，其与支架蛋白IQGAP1结合后，引起后者构象改变，导致ERK无法激活，是该领域的新突破。我们还发现，FOXO1在前列腺癌中存在丢失现象，肿瘤级别越高丢失越严重。因此，FOXO1丢失导致ERK信号不受限的激活，或是Warburg效应的始动因素。.本研究拟在细胞和动物水平，采用生化、细胞分子生物学方法，系统阐明磷酸化FOXO1及一个模拟磷酸化FOXO1的P2SE小肽对前列腺癌Warburg效应的抑制作用及机制。本研究将完善Warburg效应的调控网络，并为自主研发的小肽向临床转化奠定科学基础。

晚期前列腺癌对现有治疗方法均不敏感，演进机制不明。Warburg效应促进肿瘤生长的理论从代谢学角度认识肿瘤，是最新的热点问题。丙酮酸激酶M2是Warburg效应发生的关键，受ERK信号调节，但始动环节不明。传统认为，叉头转录因子O1（FOXO1）磷酸化后即失去功能。我们前期发现，磷酸化FOXO1仍具肿瘤抑制作用，其与支架蛋白IQGAP1结合后，引起后者构象改变，导致ERK信号无法激活，是该领域的新突破。我们前期的研究还发现，FOXO1在前列腺癌中存在丢失现象，肿瘤级别越高丢失越严重。因此，FOXO1丢失导致ERK信号不受限的激活，可能是Warburg效应的始动因素，本项目以此为目标展开了研究。.本研究在细胞和动物水平，采用生化、细胞分子生物学等方法，系统阐述明了磷酸化FOXO1在前列腺癌中丢失导致ERK信号激活，从而激发了肿瘤中的Warburg效应。本研究所模拟的一种磷酸化FOXO1——P2SE小肽，可以有效地抑制ERK信号激活，从而抑制了前列腺癌的Warburg效应。本研究不仅完善了Warburg效应的调控网络机制，并为自主研发的小肽向临床转化奠定了科学基础，同时本项目成功申请获批一项关于该小肽的国家发明专利，为后续成果转化打下知识产权的基础。