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

doi:10.1016/j.celrep.2019.08.087

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

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

Authors

Tsuyoshi Osawa¹, Teppei Shimamura², Kyoko Saito³, Yoko Hasegawa⁴, Naoko Ishii⁴, Miyuki Nishida⁴, Ritsuko Ando⁴, Ayano Kondo⁵, Muyassar Anwar⁵, Rika Tsuchida⁴, Shinjiro Hino⁶, Akihisa Sakamoto⁶, Kaori Igarashi⁷, Kaori Saitoh⁷, Keiko Kato⁷, Keiko Endo⁷, Shotaro Yamano⁸, Yasuharu Kanki⁹, Yoshihiro Matsumura¹⁰, Takashi Minami¹¹, Toshiya Tanaka¹², Motonobu Anai¹², Youichiro Wada⁹, Hideki Wanibuchi⁸, Mitsuhiro Hayashi¹³, Akinobu Hamada¹⁴, Masayuki Yoshida¹⁵, Shinichi Yachida¹⁶, Mitsuyoshi Nakao⁶, Juro Sakai¹⁷, Hiroyuki Aburatani⁵, Masabumi Shibuya¹⁸, Kentaro Hanada³, Satoru Miyano¹⁹, Tomoyoshi Soga²⁰, Tatsuhiko Kodama²¹

Affiliations

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.

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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Line, Tumor
Disease Progression
Down-Regulation / genetics*
Ethanolamines / metabolism*
Glutamine / metabolism*
HeLa Cells
Hep G2 Cells
Human Umbilical Vein Endothelial Cells
Humans
MCF-7 Cells
Mice, Inbred C57BL
Proto-Oncogene Proteins c-ets / genetics
RNA Nucleotidyltransferases / genetics*
Starvation / metabolism*
Transcription, Genetic / genetics

Substances

Ethanolamines
Proto-Oncogene Proteins c-ets
Glutamine
phosphorylethanolamine
RNA Nucleotidyltransferases
Ethanolamine-phosphate cytidylyltransferase