Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2
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 metab...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-10-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719311490 |
| _version_ | 1818597408231129088 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Tsuyoshi Osawa |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-16T11:47:20Z |
| format | Article |
| id | doaj.art-c34c33e130784dc786b3ca3e8ed731d1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-16T11:47:20Z |
| publishDate | 2019-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c34c33e130784dc786b3ca3e8ed731d12022-12-21T22:32:48ZengElsevierCell Reports2211-12472019-10-0129189103.e7Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2Tsuyoshi Osawa0Teppei Shimamura1Kyoko Saito2Yoko Hasegawa3Naoko Ishii4Miyuki Nishida5Ritsuko Ando6Ayano Kondo7Muyassar Anwar8Rika Tsuchida9Shinjiro Hino10Akihisa Sakamoto11Kaori Igarashi12Kaori Saitoh13Keiko Kato14Keiko Endo15Shotaro Yamano16Yasuharu Kanki17Yoshihiro Matsumura18Takashi Minami19Toshiya Tanaka20Motonobu Anai21Youichiro Wada22Hideki Wanibuchi23Mitsuhiro Hayashi24Akinobu Hamada25Masayuki Yoshida26Shinichi Yachida27Mitsuyoshi Nakao28Juro Sakai29Hiroyuki Aburatani30Masabumi Shibuya31Kentaro Hanada32Satoru Miyano33Tomoyoshi Soga34Tatsuhiko Kodama35Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan; Corresponding authorDepartment of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Corresponding authorDepartment of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, JapanDivision of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, JapanDivision of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, JapanDivision of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, JapanDivision of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, JapanDivision of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, JapanDivision of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, JapanDivision of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, JapanDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, JapanDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, JapanInstitute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, JapanInstitute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, JapanInstitute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, JapanInstitute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, JapanDepartment of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, JapanIsotope Science Center, The University of Tokyo, Tokyo 113-0032, JapanDivision of Metabolic Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, JapanDivision of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, JapanLaboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, JapanLaboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, JapanIsotope Science Center, The University of Tokyo, Tokyo 113-0032, JapanDepartment of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, JapanDivision 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, JapanDivision of Molecular Pharmacology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, JapanDepartment of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, JapanDepartment of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka 565-0871, JapanDepartment of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, JapanDivision 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, JapanDivision of Genome Science, RCAST, The University of Tokyo, Tokyo 153-8904, JapanInstitute of Physiology and Medicine, Jobu University, 634-1 Toyazuka-machi, Isesaki, Gunma 372-8588, JapanDepartment of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Toyama, Shinjuku-ku, Tokyo 162-8640, JapanHuman Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanInstitute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan; Corresponding authorLaboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, Tokyo 153-8904, Japan; Corresponding authorSummary: 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 biosynthesishttp://www.sciencedirect.com/science/article/pii/S2211124719311490 |
| spellingShingle | 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 Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 Cell Reports |
| title | Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 |
| title_full | Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 |
| title_fullStr | Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 |
| title_full_unstemmed | Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 |
| title_short | Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2 |
| title_sort | phosphoethanolamine accumulation protects cancer cells under glutamine starvation through downregulation of pcyt2 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719311490 |
| work_keys_str_mv | AT tsuyoshiosawa phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT teppeishimamura phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT kyokosaito phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT yokohasegawa phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT naokoishii phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT miyukinishida phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT ritsukoando phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT ayanokondo phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT muyassaranwar phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT rikatsuchida phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT shinjirohino phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT akihisasakamoto phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT kaoriigarashi phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT kaorisaitoh phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT keikokato phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT keikoendo phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT shotaroyamano phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT yasuharukanki phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT yoshihiromatsumura phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT takashiminami phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT toshiyatanaka phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT motonobuanai phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT youichirowada phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT hidekiwanibuchi phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT mitsuhirohayashi phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT akinobuhamada phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT masayukiyoshida phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT shinichiyachida phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT mitsuyoshinakao phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT jurosakai phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT hiroyukiaburatani phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT masabumishibuya phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT kentarohanada phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT satorumiyano phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT tomoyoshisoga phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 AT tatsuhikokodama phosphoethanolamineaccumulationprotectscancercellsunderglutaminestarvationthroughdownregulationofpcyt2 |