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 and other oxidants. We show here that ccRCC xenograft tumors under the renal capsule exhibit enhanced oxidative stress compared with 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, and increased 8-oxo-7,8-dihydro-2'-deoxyguanosine, 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 compared with 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 patients with ccRCC who are likely to respond to glutaminase inhibitors in the clinic. Cancer Res; 77(23); 6746-58. ©2017 AACR.
Highlights
Oxidative stress is characterized as an imbalance between the generation of cellular oxidants and the process of scavenging their byproducts
The GSH/GSSG ratios were significantly decreased in tumor tissues as compared with tissues from the normal right kidney (RK) but with less extent in the adjacent normal left kidney (LK) (Fig. 1C), indicating that the RCC microenvironment was associated with higher levels of oxidative stress compared with normal kidney tissues
We evaluated levels of nuclear factor erythroid-related factor 2 (NRF2), a transcription factor that controls enzymes that regulate the antioxidant response in cells [46], and we used indirect measurements of oxidative damage to DNA by measuring levels of 8oxodG [47]
Summary
Oxidative stress is characterized as an imbalance between the generation of cellular oxidants and the process of scavenging their byproducts. If this redox balance is perturbed, damage of essential components of the cell, including proteins, lipids, and DNA, will occur, thereby disturbing organismal homeostasis and leading to a variety of adverse outcomes including oncogenesis and progression of cancer [1,2,3,4]. During periods or locations of environmental stress, such as a highly metabolically active malignancy, excessive ROS are produced, which can lead to structural damage within the cell and can hinder the progression of the malignancy [7]; in such cases, cancer cells often compensate for the higher levels of intrinsic ROS by evolving adaptive mechanisms that increase the cellular antioxidants and corresponding pathways [8]. The balance of pro- and antioxidative systems needs to be finely tuned for the "success" of the tumor, but this same system has the potential to be subverted for therapeutic benefit
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