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Title: Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging

Journal Article · · Cancer Research
 [1];  [2];  [1];  [3];  [2];  [4];  [5];  [6]
  1. Univ. of California, Davis, CA (United States). Division of Nephrology
  2. Univ. of Texas Health Science Center, San Antonio, TX (United States)
  3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  4. Univ. of California, Davis, Sacramento, CA (United States). Dept. of Radiology; Univ. of California, Davis, CA (United States). Center for Molecular and Genomic Imaging
  5. Univ. of California, Davis, CA (United States). Center for Molecular and Genomic Imaging; Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology; Univ. of California, Davis, CA (United States). Dept. of Biomedical Engineering
  6. Univ. of California, Davis, CA (United States). Comprehensive Cancer Center; Univ. of California, Davis, Sacramento, CA (United States). Dept.; VA Northern California Health Care System, Sacramento, CA (United States). Medical Service
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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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE
Contributing Organization:
Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology
Grant/Contract Number:
AC52-07NA27344
OSTI ID:
1438775
Report Number(s):
LLNL-JRNL--725543
Journal Information:
Cancer Research, Journal Name: Cancer Research Journal Issue: 23 Vol. 77; ISSN 0008-5472
Publisher:
American Association for Cancer ResearchCopyright Statement
Country of Publication:
United States
Language:
English

Cited By (10)

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers journal April 2019
Warburg and Krebs and related effects in cancer journal January 2019
Oncometabolites in renal cancer journal October 2019
Metabolomic insights into pathophysiological mechanisms and biomarker discovery in clear cell renal cell carcinoma journal May 2019
Targeting glutamine metabolism and redox state for leukemia therapy posted_content April 2018
Papillary renal cell carcinomas rewire glutathione metabolism and are deficient in anabolic glucose synthesis posted_content May 2019
Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis journal December 2018
Functional characteristics of autophagy in pancreatic cancer induced by glutamate metabolism in pancreatic stellate cells journal December 2019
Renal cell carcinoma: a review of biology and pathophysiology journal January 2018
Oncometabolites in renal cancer text January 2019

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