Cell Reports (Aug 2023)
Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy
- Manabu Kodama,
- Gouji Toyokawa,
- Osamu Sugahara,
- Shigeaki Sugiyama,
- Naoki Haratake,
- Yuichi Yamada,
- Reona Wada,
- Shinkichi Takamori,
- Mototsugu Shimokawa,
- Tomoyoshi Takenaka,
- Tetsuzo Tagawa,
- Hiroki Kittaka,
- Takeshi Tsuruda,
- Kentaro Tanaka,
- Yushiro Komatsu,
- Keisuke Nakata,
- Yuri Imado,
- Koji Yamazaki,
- Isamu Okamoto,
- Yoshinao Oda,
- Masatomo Takahashi,
- Yoshihiro Izumi,
- Takeshi Bamba,
- Hideyuki Shimizu,
- Tomoharu Yoshizumi,
- Keiichi I. Nakayama
Affiliations
- Manabu Kodama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Gouji Toyokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Thoracic Surgery, NHO Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-0065, Japan
- Osamu Sugahara
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Shigeaki Sugiyama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Naoki Haratake
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Yuichi Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Reona Wada
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Shinkichi Takamori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minamikogushi, Ube, Yamaguchi 755-8505, Japan
- Tomoyoshi Takenaka
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Tetsuzo Tagawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Hiroki Kittaka
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; LSI Medience Corporation, 1-13-4 Uchikanda, Chiyoda-ku, Tokyo 101-8517, Japan
- Takeshi Tsuruda
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Kentaro Tanaka
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Yushiro Komatsu
- Department of AI Systems Medicine, M&D Data Science Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
- Keisuke Nakata
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Yuri Imado
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Koji Yamazaki
- Department of Thoracic Surgery, NHO Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-ku, Fukuoka 810-0065, Japan
- Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Masatomo Takahashi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Yoshihiro Izumi
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Takeshi Bamba
- Division of Metabolomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Hideyuki Shimizu
- Department of AI Systems Medicine, M&D Data Science Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan
- Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
- Keiichi I. Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Anticancer Strategies Laboratory, TMDU Advanced Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 8
p. 112899
Abstract
Summary: Small cell lung cancer (SCLC) is one of the deadliest human cancers, with a 5-year survival rate of ∼7%. Here, we performed a targeted proteomics analysis of human SCLC samples and thereby identified hypoxanthine phosphoribosyltransferase 1 (HPRT1) in the salvage purine synthesis pathway as a factor that contributes to SCLC malignancy by promoting cell survival in a glutamine-starved environment. Inhibition of HPRT1 by 6-mercaptopurine (6-MP) in combination with methotrexate (MTX), which blocks the de novo purine synthesis pathway, attenuated the growth of SCLC in mouse xenograft models. Moreover, modulation of host glutamine anabolism with the glutamine synthetase inhibitor methionine sulfoximine (MSO) in combination with 6-MP and MTX treatment resulted in marked tumor suppression and prolongation of host survival. Our results thus suggest that modulation of host glutamine anabolism combined with simultaneous inhibition of the de novo and salvage purine synthesis pathways may be of therapeutic benefit for SCLC.
