Cell Reports (Oct 2019)
Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2
- Tsuyoshi Osawa,
- Teppei Shimamura,
- Kyoko Saito,
- Yoko Hasegawa,
- Naoko Ishii,
- Miyuki Nishida,
- Ritsuko Ando,
- Ayano Kondo,
- Muyassar Anwar,
- Rika Tsuchida,
- Shinjiro Hino,
- Akihisa Sakamoto,
- Kaori Igarashi,
- Kaori Saitoh,
- Keiko Kato,
- Keiko Endo,
- Shotaro Yamano,
- Yasuharu Kanki,
- Yoshihiro Matsumura,
- Takashi Minami,
- Toshiya Tanaka,
- Motonobu Anai,
- Youichiro Wada,
- Hideki Wanibuchi,
- Mitsuhiro Hayashi,
- Akinobu Hamada,
- Masayuki Yoshida,
- Shinichi Yachida,
- Mitsuyoshi Nakao,
- Juro Sakai,
- Hiroyuki Aburatani,
- Masabumi Shibuya,
- Kentaro Hanada,
- Satoru Miyano,
- Tomoyoshi Soga,
- Tatsuhiko Kodama
Affiliations
- Tsuyoshi Osawa
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan; Corresponding author
- Teppei Shimamura
- Department of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Corresponding author
- Kyoko Saito
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
- Yoko Hasegawa
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
- Naoko Ishii
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
- Miyuki Nishida
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
- Ritsuko Ando
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
- Ayano Kondo
- Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Muyassar Anwar
- Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Rika Tsuchida
- Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
- Shinjiro Hino
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Akihisa Sakamoto
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Kaori Igarashi
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
- Kaori Saitoh
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
- Keiko Kato
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
- Keiko Endo
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
- Shotaro Yamano
- Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
- Yasuharu Kanki
- Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan
- Yoshihiro Matsumura
- Division of Metabolic Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Takashi Minami
- Division of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan
- Toshiya Tanaka
- Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Motonobu Anai
- Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Youichiro Wada
- Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan
- Hideki Wanibuchi
- Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
- Mitsuhiro Hayashi
- 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
- Akinobu Hamada
- Division of Molecular Pharmacology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
- Masayuki Yoshida
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan
- Shinichi Yachida
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
- Mitsuyoshi Nakao
- Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Juro Sakai
- 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
- Hiroyuki Aburatani
- Division of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, Japan
- Masabumi Shibuya
- Institute of Physiology and Medicine, Jobu University, 634-1 Toyazuka-machi, Isesaki, Gunma 372-8588, Japan
- Kentaro Hanada
- Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
- Satoru Miyano
- Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
- Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan; Corresponding author
- Tatsuhiko Kodama
- Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan; Corresponding author
- Journal volume & issue
-
Vol. 29,
no. 1
pp. 89 – 103.e7
Abstract
Summary: 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. : Osawa et al. find that accumulation of phosphoethanolamine (PEtn) protects cancer cells under glutamine starvation through the downregulation of PCYT2. Glutamine regulates PE biosynthesis through PCYT2, resulting in pro-tumorigenic metabolite PEtn accumulation. PEtn stimulates the tolerance of cancer cells to starvation, and lowered PCYT2 expression correlates with decreased survival in patients. Keywords: cancer metabolism, tumor microenvironments, hypoxia, nutrient starvation, glutamine deprivation, amino acids, phosphoethanolamine, PCYT2, PE biosynthesis
