Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging.
Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging.
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DOI：
10.1158/0008-5472.can-17-0930
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发表时间：
2017-12-01
期刊：
影响因子：
11.2
通讯作者：
Weiss RH
中科院分区：
文献类型：
--
作者：
Abu Aboud O;Habib SL;Trott J;Stewart B;Liang S;Chaudhari AJ;Sutcliffe J;Weiss RH
许多癌症似乎会激活内在的抗氧化系统作为对抗氧化应激的一种手段。一些癌症，如透明细胞肾细胞癌 (ccRCC)，需要外源性谷氨酰胺生长，并表现出重新编程的谷氨酰胺代谢，至少部分归因于谷胱甘肽途径，谷胱甘肽途径是一种有效的细胞缓冲系统，可以抵消活性氧 (ROS) 和其他氧化剂。我们在此表明，与邻近正常组织和对侧肾脏相比，肾囊下的 ccRCC 异种移植肿瘤表现出增强的氧化应激。用 CB-839 或 BPTES 抑制谷氨酰胺酶后，RCC 细胞系 SN12PM-6-1 (SN12) 和 786-O 表现出存活率下降和明显的细胞凋亡，与 GSH/GSSG 比率降低、核因子红细胞相关因子 2 (NRF2) 增加以及 DNA 标记物 8-oxo-7,8-二氢-2'-脱氧鸟苷 (8-oxodG) 增加相关损坏。当用 CB-839 处理时，SN12 肿瘤异种移植物显示出生长下降。此外，PET成像证实，与原位小鼠模型中的肾脏相比，ccRCC肿瘤表现出18F-(2S,4R)4-氟谷氨酰胺(18F-FGln)的肿瘤摄取增加。该技术可用于跟踪体内 ccRCC 代谢的变化。这些范例的进一步发展将带来谷氨酰胺酶抑制剂的新治疗选择，以及利用 PET 来识别和管理临床上可能对谷氨酰胺酶抑制剂有反应的 ccRCC 患者。
Many cancers appear to activate intrinsic antioxidant systems as a means to counteract oxidative stress. Some cancers, such as clear cell renal cell carcinoma (ccRCC), require exogenous glutamine for growth and exhibit reprogrammed glutamine metabolism, at least in part due to the glutathione pathway, an efficient cellular buffering system that counteracts reactive oxygen species (ROS) and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared to adjacent normal tissue and the contralateral kidney. Upon glutaminase inhibition with CB-839 or BPTES, the RCC cell lines SN12PM-6-1 (SN12) and 786-O exhibited decreased survival and pronounced apoptosis associated with a decreased GSH/GSSG ratio, augmented nuclear factor erythroid related factor 2 (NRF2), and increased 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a marker of DNA damage. SN12 tumor xenografts showed decreased growth when treated with CB-839. Furthermore, PET imaging confirmed that ccRCC tumors exhibited increased tumoral uptake of 18F-(2S,4R)4- fluoroglutamine (18F-FGln) compared to the kidney in the orthotopic mouse model. This technique can be utilized to follow changes in ccRCC metabolism in vivo. Further development of these paradigms will lead to new treatment options with glutaminase inhibitors and the utility of PET to identify and manage ccRCC patients who are likely to respond to glutaminase inhibitors in the clinic.