Antioxidants Accelerate Lung Cancer Progression in Mice

Science translational medicine (Impact Factor: 15.84). 01/2014; 6(221):221ra15. DOI: 10.1126/scitranslmed.3007653
Source: PubMed


Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

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    • "Next, we tested eIF4E dose requirements in the setting of in vivo tumorigenesis driven by endogenous expression of oncogenic KRas. Importantly, the ability to properly respond to and control ROS is critical for lung cancer driven by endogenous expression of oncogenic KRas (DeNicola et al., 2011; Sayin et al., 2014). Thus, we asked what effect genetically reducing the dose of eIF4E by 50% would have in the KRas LA2 model of lung cancer (Figure 7A) (Johnson et al., 2001). "
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    ABSTRACT: eIF4E, the major cap-binding protein, has long been considered limiting for translating the mammalian genome. However, the eIF4E dose requirement at an organismal level remains unexplored. By generating an Eif4e haploinsufficient mouse, we found that a 50% reduction in eIF4E expression, while compatible with normal development and global protein synthesis, significantly impeded cellular transformation. Genome-wide translational profiling uncovered a translational program induced by oncogenic transformation and revealed a critical role for the dose of eIF4E, specifically in translating a network of mRNAs enriched for a unique 5' UTR signature. In particular, we demonstrate that the dose of eIF4E is essential for translating mRNAs that regulate reactive oxygen species, fueling transformation and cancer cell survival in vivo. Our findings indicate eIF4E is maintained at levels in excess for normal development that are hijacked by cancer cells to drive a translational program supporting tumorigenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 06/2015; 162(1). DOI:10.1016/j.cell.2015.05.049 · 32.24 Impact Factor
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    • "However, we observed decreased ROS production in OTA treatment groups at 4 and 13 weeks. Reduced ROS can facilitate tumor cell proliferation (Sayin et al., 2014). In addition, increased PCNA of the kidneys in the highdose group suggested that the rat kidney is likely to be the target for OTA carcinogenicity. "
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    • "Results obtained from randomized clinical trials, however, were inconsistent and in some circumstances have indicated that antioxidants increase cancer risk (Klein et al., 2011; Watson, 2013). Moreover, it was reported that supplementing the diet with the antioxidants N-acetylcysteine and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer, by reduction of ROS, DNA damage, and p53 expression (Sayin et al., 2014). On the contrary, the use of small molecules derived from diet that alter the levels of ROS, such as diallyl disulfide, polyphenols, isothiocyanates, and terpenoids has been suggested for the treatment of cancer by promoting ROS generation and GSH depletion in cancer cells (Filomeni et al., 2003; Shankar et al., 2006; Trachootham et al., 2006; Yue et al., 2006; Aquilano et al., 2010). "
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