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

Abstract

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:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
Contributing Org.:
Univ. of California, Davis, CA (United States). Dept. of Internal Medicine, Division of Hematology and Oncology
OSTI Identifier:
1438775
Report Number(s):
LLNL-JRNL-725543
Journal ID: ISSN 0008-5472; TRN: US1900522
Grant/Contract Number:  
AC52-07NA27344
Resource 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
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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., 2017. 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. Wed . "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}
}

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Figures / Tables:

Figure 1 Figure 1:

RCC tumors show higher oxidative stress as compared to adjacent normal and contralateral renal tissues.

A. SN12-PM6-1 (SN12) cells were implanted under the renal capsule of the left kidney in SCID mice and whole body bioluminescence imaging was acquired in the three animal experiments as described in Materialsmore » and Methods. A representative imaged mouse is shown.

B. The metabolites GSH and GSSG were measured in RCC tumors, tumor-adjacent normal tissue in left kidney (LK), and untouched right kidney (RK) in untreated mice (n=3). Data are mean ± SEM. *p<0.05 compared to tumor tissue. For GSH, p=0.008 for tumor vs RK and p=0.032 for tumor vs LK. For GSSG p=0.006 for tumor vs RK and p=0.071 for tumor vs LK). Results shown are representative of at least three independent experiments

C. The ratio of GSH/GSSG from the same measurements in Fig.1B were calculated in RCC tumors, adjacent renal tissue in left kidney (LK) and tissue from right kidney (RK) (n=3/group). Error bars are SEM. *p<0.05 compared to tumor tissue. For tumor vs RK p=.023 , tumor vs LK p=.069. Results shown are representative of at least two independent experiments

D. Representative sections of normal right kidney and tumor tissues were subjected to immunoperoxidase staining for NRF2.

E. Representative sections of normal and tumor kidney tissues were subjected to immunofluorescence staining for 8-oxodG and propidium iodide (PI; nuclear stain).

F. Quantitation of 8-oxodG levels were measured in the DNA of RCC tumors and normal kidney tissues from 5 mice, which were randomly selected from 10 untreated mice, and the average is shown. Data are mean ±SEM. *p<0.05 tumor compared to normal kidney (p=.006).

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