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. 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. 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. 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.

中文翻译：

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ESM1 通过利用缺氧肿瘤微环境中 PKM2 依赖的 Warburg 效应增强卵巢癌中的脂肪酸合成和血管拟态

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增殖和血管生成中发挥重要作用。然而，ESM1 在 OC 患者的代谢重编程和缺氧微环境中 VM 中的作用尚未确定。液相色谱与串联质谱联用用于分析 CAOV3 和 OV90 细胞。通过 GST Pull-down、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。通过小管形成、transwell实验、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。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 是 PKM2 和 UBA2 之间相互作用的重要介体，促进 PKM2 的 SUMO 化以及随后 PKM2 二聚体的形成。这一过程促进了 Warburg 效应并促进 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能有效抑制ESM1和PKM2之间的分子相互作用，从而阻止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。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 化诱导二聚化，从而促进 OC Warburg 效应和 VM。