Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Department of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Cell Rep. 2019 Oct 1;29(1):89-103.e7. doi: 10.1016/j.celrep.2019.08.087.
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.
耐受严重的肿瘤微环境，包括缺氧和营养饥饿，是侵袭性癌细胞的共同特征，可以作为治疗靶点。然而，支持营养饥饿时癌细胞的代谢改变还不是很清楚。在这里，通过全面的代谢组学分析，我们发现谷氨酰胺剥夺通过下调磷酸乙醇胺胞苷转移酶（PCYT2）导致磷酸乙醇胺（PEtn）在癌细胞中的积累，PCYT2 是磷酸乙醇胺生物合成的限速酶。PEtn 的积累与营养饥饿下的肿瘤生长相关。转录因子 ELF3 的下调部分介导了 PCYT2 的抑制。此外，PCYT2 的过表达降低了 PEtn 水平和肿瘤生长。此外，人乳腺癌组织中 PEtn 积累和 PCYT2 下调与预后不良相关。因此，我们表明，通过 ELF3-PCYT2 轴调节 PE 生物合成，谷氨酰胺剥夺可导致肿瘤进展。此外，操纵谷氨酰胺反应基因可能是限制癌症进展的一种治疗方法。
