宿主谷氨酰胺合成代谢的调节增强了小细胞肺癌对化疗的敏感性。

Modulation of host glutamine anabolism enhances the sensitivity of small cell lung cancer to chemotherapy.

作者信息

Kodama Manabu, Toyokawa Gouji, Sugahara Osamu, Sugiyama Shigeaki, Haratake Naoki, Yamada Yuichi, Wada Reona, Takamori Shinkichi, Shimokawa Mototsugu, Takenaka Tomoyoshi, Tagawa Tetsuzo, Kittaka Hiroki, Tsuruda Takeshi, Tanaka Kentaro, Komatsu Yushiro, Nakata Keisuke, Imado Yuri, Yamazaki Koji, Okamoto Isamu, Oda Yoshinao, Takahashi Masatomo, Izumi Yoshihiro, Bamba Takeshi, Shimizu Hideyuki, Yoshizumi Tomoharu, Nakayama Keiichi I

机构信息

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

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.

出版信息

Cell Rep. 2023 Aug 29;42(8):112899. doi: 10.1016/j.celrep.2023.112899. Epub 2023 Aug 1.

DOI:10.1016/j.celrep.2023.112899

PMID:37531252

Abstract

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.

摘要

小细胞肺癌（SCLC）是最致命的人类癌症之一，5年生存率约为7%。在此，我们对人类SCLC样本进行了靶向蛋白质组学分析，从而在补救嘌呤合成途径中鉴定出次黄嘌呤磷酸核糖基转移酶1（HPRT1），它是通过在谷氨酰胺缺乏的环境中促进细胞存活来促进SCLC恶性肿瘤发展的一个因素。在小鼠异种移植模型中，6-巯基嘌呤（6-MP）与甲氨蝶呤（MTX）联合使用（MTX可阻断从头嘌呤合成途径）抑制HPRT1，可减弱SCLC的生长。此外，用谷氨酰胺合成酶抑制剂蛋氨酸亚砜胺（MSO）调节宿主谷氨酰胺合成代谢，并联合6-MP和MTX治疗，可显著抑制肿瘤并延长宿主生存期。因此，我们的结果表明，调节宿主谷氨酰胺合成代谢并同时抑制从头和补救嘌呤合成途径可能对SCLC具有治疗益处。