ESM1 通过在缺氧肿瘤微环境中利用 PKM2 依赖性瓦博格效应增强脂肪酸合成和血管拟态在卵巢癌中的作用。
ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.
机构信息
Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China.
Department of Cardiology, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China.
出版信息
Mol Cancer. 2024 May 8;23(1):94. doi: 10.1186/s12943-024-02009-8.
BACKGROUND
The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined.
METHODS
Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments.
RESULTS
Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry.
CONCLUSION
Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.
背景
缺氧肿瘤微环境是促进卵巢癌（OC）患者代谢重编程和血管拟态（VM）的关键因素。ESM1 是一种分泌蛋白，在促进 OC 细胞增殖和血管生成中发挥重要作用。然而，ESM1 在 OC 患者缺氧微环境中的代谢重编程和 VM 中的作用尚未确定。
方法
使用液相色谱串联质谱法分析 CAOV3 和 OV90 细胞。通过 GST 下拉、Co-IP 和分子对接检测 ESM1、PKM2、UBA2 和 SUMO1 之间的相互作用。基于 ECAR 实验分析 ESM1-PKM2 轴对细胞葡萄糖代谢的影响。通过管形成、Transwell 测定、RT-PCR、Western blot、免疫荧光和体内异种移植肿瘤实验检测信号轴对 OC 细胞的生物学效应。
结果
我们的研究结果表明，缺氧通过 HIF-1α 的转录诱导 ESM1 表达上调。ESM1 作为 PKM2 和 UBA2 之间相互作用的关键介质，促进 PKM2 的 SUMO 化和随后 PKM2 二聚体的形成。这一过程促进了Warburg 效应，并促进了 PKM2 的核转位，最终导致 STAT3 的磷酸化。这些分子事件有助于促进卵巢癌糖酵解和血管生成拟态。此外，我们的研究表明，紫草素可有效抑制 ESM1 和 PKM2 之间的分子相互作用，从而防止 PKM2 二聚体的形成，从而抑制卵巢癌糖酵解、脂肪酸合成和血管生成拟态。
结论
我们的研究结果表明，缺氧通过 HIF-1α 的转录调节增加 ESM1 的表达，通过 PKM2 SUMO 化诱导二聚体形成，从而促进 OC 的 Warburg 效应和 VM。
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