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

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 aremore » likely to respond to glutaminase inhibitors in the clinic.« less
Authors:
 [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
Publication Date:
Report Number(s):
LLNL-JRNL-725543
Journal ID: ISSN 0008-5472
Grant/Contract Number:
AC52-07NA27344
Type:
Accepted Manuscript
Journal Name:
Cancer Research
Additional Journal Information:
Journal Volume: 77; Journal Issue: 23; Journal ID: ISSN 0008-5472
Publisher:
American Association for Cancer Research
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org:
USDOE
Contributing Orgs:
Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1438775

Abu Aboud, Omran, Habib, Samy L., Trott, Josephine, Stewart, Benjamin, Liang, Sitai, Chaudhari, Abhijit J., Sutcliffe, Julie, and Weiss, Robert H.. Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging. United States: N. p., Web. doi:10.1158/0008-5472.CAN-17-0930.
Abu Aboud, Omran, Habib, Samy L., Trott, Josephine, Stewart, Benjamin, Liang, Sitai, Chaudhari, Abhijit J., Sutcliffe, Julie, & Weiss, Robert H.. Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging. United States. doi:10.1158/0008-5472.CAN-17-0930.
Abu Aboud, Omran, Habib, Samy L., Trott, Josephine, Stewart, Benjamin, Liang, Sitai, Chaudhari, Abhijit J., Sutcliffe, Julie, and Weiss, Robert H.. 2017. "Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging". United States. doi:10.1158/0008-5472.CAN-17-0930. https://www.osti.gov/servlets/purl/1438775.
@article{osti_1438775,
title = {Glutamine Addiction in Kidney Cancer Suppresses Oxidative Stress and Can Be Exploited for Real-Time Imaging},
author = {Abu Aboud, Omran and Habib, Samy L. and Trott, Josephine and Stewart, Benjamin and Liang, Sitai and Chaudhari, Abhijit J. and Sutcliffe, Julie and Weiss, Robert H.},
abstractNote = {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.},
doi = {10.1158/0008-5472.CAN-17-0930},
journal = {Cancer Research},
number = 23,
volume = 77,
place = {United States},
year = {2017},
month = {10}
}