Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2
Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2
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DOI：
10.1016/j.celrep.2019.08.087
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发表时间：
2019-10-01
期刊：
影响因子：
8.8
通讯作者：
Kodama, Tatsuhiko
中科院分区：
文献类型：
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作者：
Osawa, Tsuyoshi;Shimamura, Teppei;Kodama, Tatsuhiko
对严重的肿瘤微环境（包括缺氧和营养饥饿）的耐受性是侵袭性癌细胞的共同特征，并且可以被靶向。然而，营养饥饿时支持癌细胞的代谢改变还没有得到很好的理解。在这里，通过全面的代谢组学分析，我们表明，谷氨酰胺剥夺导致磷酸乙醇胺（PEtn）积累在癌细胞通过下调PEtn胞苷酰转移酶（PCYT 2），磷脂酰乙醇胺生物合成的限速酶。PEtn积累与营养饥饿下的肿瘤生长相关。PCYT 2抑制部分由转录因子ELF 3的下调介导。此外，PCYT 2过表达降低了PEtn水平和肿瘤生长。此外，人乳腺肿瘤中PEtn积累和PCYT 2下调与不良预后相关。因此，我们表明，谷氨酰胺剥夺导致肿瘤的进展，通过调节PE生物合成通过ELF 3-PCYT 2轴。此外，操纵谷氨酰胺反应基因可能是一种限制癌症进展的治疗方法。
Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis. PEtn accumulation correlated with tumor growth under nutrient starvation. PCYT2 suppression was partially mediated by downregulation of the transcription factor ELF3. Furthermore, PCYT2 overexpression reduced PEtn levels and tumor growth. In addition, PEtn accumulation and PCYT2 downregulation in human breast tumors correlated with poor prognosis. Thus, we show that glutamine deprivation leads to tumor progression by regulating PE biosynthesis via the ELF3-PCYT2 axis. Furthermore, manipulating glutamine-responsive genes could be a therapeutic approach to limit cancer progression.