Rationale: Cancer cells rely on glucose metabolism for fulfilling their high energy demands. We previously reported that monoethanolamine (Etn), an orally deliverable lipid formulation, reduced intracellular glucose and glutamine levels in prostate cancer (PCa). Glucose deprivation upon Etn treatment exacerbated metabolic stress in PCa, thereby enhancing cell death. Moreover, Etn was potent in inhibiting tumor growth in a PCa xenograft model. However, the precise mechanisms underlying Etn-induced metabolic stress in PCa remain elusive. The purpose of the present study was to elucidate the mechanisms contributing to Etn-mediated metabolic rewiring in PCa. Methods: Glucose transporters (GLUTs) facilitate glucose transport across the plasma membrane. Thus, we assessed the expression of GLUTs and the internalization of GLUT1 in PCa. We also evaluated the effects of Etn on membrane dynamics, mitochondrial structure and function, lipid droplet density, autophagy, and apoptosis in PCa cells. Results: Compared to other GLUTs, GLUT1 was highly upregulated in PCa. We observed enhanced GLUT1 internalization, altered membrane dynamics, and perturbed mitochondrial structure and function upon Etn treatment. Etn-induced bioenergetic stress enhanced lipolysis, decreased lipid droplet density, promoted accumulation of autophagosomes, and increased apoptosis. Conclusion: We provide the first evidence that Etn alters GLUT1 trafficking leading to metabolic stress in PCa. By upregulating phosphatidylethanolamine (PE), Etn modulates membrane fluidity and affects mitochondrial structure and function. Etn also induces autophagy in PCa cells, thereby promoting apoptosis. These data strongly suggest that Etn rewires cellular bioenergetics and could serve as a promising anticancer agent for PCa.

中文翻译：

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单乙醇胺诱导的葡萄糖剥夺通过前列腺癌的代谢重新布线促进细胞凋亡。

基本原理：癌细胞依靠葡萄糖代谢来满足其高能量需求。我们之前报道过单乙醇胺 (Etn) 是一种口服脂质制剂，可降低前列腺癌 (PCa) 中的细胞内葡萄糖和谷氨酰胺水平。Etn 治疗后的葡萄糖剥夺加剧了 PCa 的代谢压力，从而增加了细胞死亡。此外，Etn 在 PCa 异种移植模型中有效抑制肿瘤生长。然而，Etn 诱导的 PCa 代谢应激的确切机制仍然难以捉摸。本研究的目的是阐明 Etn 介导的 PCa 代谢重新布线的机制。方法：葡萄糖转运蛋白 (GLUT) 促进葡萄糖跨质膜的转运。因此，我们评估了 GLUTs 的表达和 GLUT1 在 PCa 中的内化。我们还评估了 Etn 对 PCa 细胞膜动力学、线粒体结构和功能、脂滴密度、自噬和凋亡的影响。结果：与其他 GLUTs 相比，GLUT1 在 PCa 中高度上调。我们观察到 Etn 治疗后 GLUT1 内化增强、膜动力学改变以及线粒体结构和功能受到干扰。Etn 诱导的生物能量应激增强了脂肪分解，降低了脂滴密度，促进了自噬体的积累，并增加了细胞凋亡。结论：我们提供了 Etn 改变导致 PCa 代谢应激的 GLUT1 运输的第一个证据。通过上调磷脂酰乙醇胺 (PE)，Etn 调节膜流动性并影响线粒体结构和功能。Etn 还在 PCa 细胞中诱导自噬，从而促进细胞凋亡。