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Cell Rep. 2019 Oct 1;29(1):89-103.e7. doi: 10.1016/j.celrep.2019.08.087.

Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

Author information

1
Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. Electronic address: osawa@lsbm.org.
2
Department of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: shimamura@med.nagoya-u.ac.jp.
3
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
4
Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
5
Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
6
Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan.
7
Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan.
8
Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.
9
Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
10
Division of Metabolic Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
11
Division of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan.
12
Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan.
13
Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
14
Division of Molecular Pharmacology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
15
Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
16
Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
17
Division of Metabolic Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan; Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
18
Institute of Physiology and Medicine, Jobu University, 634-1 Toyazuka-machi, Isesaki, Gunma 372-8588, Japan.
19
Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
20
Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan. Electronic address: soga@sfc.keio.ac.jp.
21
Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan. Electronic address: kodama@lsbm.org.

Abstract

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.

KEYWORDS:

PCYT2; PE biosynthesis; amino acids; cancer metabolism; glutamine deprivation; hypoxia; nutrient starvation; phosphoethanolamine; tumor microenvironments

PMID:
31577958
DOI:
10.1016/j.celrep.2019.08.087
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