Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer.
Monoethanolamine-induced glucose deprivation promotes apoptosis through metabolic rewiring in prostate cancer.
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DOI：
10.7150/thno.62724
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Aneja R
中科院分区：
文献类型：
--
作者：
Garlapati C;Joshi S;Turaga RC;Mishra M;Reid MD;Kapoor S;Artinian L;Rehder V;Aneja R
基本原理：癌细胞依赖于葡萄糖代谢来满足其高能量需求。我们以前报道过单乙醇胺（Etn），一种口服脂质制剂，可降低前列腺癌（PCa）细胞内葡萄糖和谷氨酰胺水平。Etn处理后葡萄糖剥夺加重了PCa中的代谢应激，从而增强了细胞死亡。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（GLUTs）促进葡萄糖跨膜转运。因此，我们评估了前列腺癌中GLUT的表达和GLUT 1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GLUT相比，GLUT 1在PCa中高度上调。我们观察到增强GLUT1内化，改变膜动力学，并扰动线粒体结构和功能Etn治疗后。etn诱导的生物能应激增强脂肪分解，降低脂滴密度，促进自噬体的积累，并增加细胞凋亡。结论：我们提供了Etn改变GLUT1运输导致PCa代谢应激的第一个证据。Etn通过上调磷脂酰乙醇胺（PE）调节膜流动性并影响线粒体结构和功能。Etn还诱导PCa细胞中的自噬，从而促进细胞凋亡。这些数据强烈表明，Etn重新布线细胞生物能量学，并可能作为一个有前途的抗癌剂PCa。
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.