调控寄主谷氨酰胺合成增强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.
发表日期：2023 Aug 01
作者：
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
来源：
Cell Reports
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％。在这里，我们对人类SCLC样本进行了靶向蛋白质组学分析，从而确定了嘌呤新合成途径中的高效核磷酸核糖转移酶1（HPRT1）作为促进SCLC恶性转化的因素，通过在缺氧的环境下促进细胞存活。通过用阻断新合成嘌呤途径的6-巯基嘌呤（6-MP）与甲氨蝶呤（MTX）抑制HPRT1，能够减弱小鼠异种移植模型中SCLC的生长。此外，通过用谷氨酰胺合成酶抑制剂亚硫酸亮氧酰亚胺（MSO）调节宿主谷氨酰胺代谢，并与6-MP和MTX联合治疗，能够显著抑制肿瘤生长并延长宿主的生存期。因此，我们的研究结果表明，联合调节宿主谷氨酰胺代谢以及同时抑制新合成和修复嘌呤合成途径可能对SCLC治疗有益。
版权所有 © 2023 The Author(s)。由Elsevier Inc.出版。保留所有权利。
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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.