Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

Rodic, Stefan; Vincent, Mark

doi:10.1002/ijc.31069

Cited by 152 publications

(117 citation statements)

References 122 publications

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“…Furthermore, gene‐set enrichment analyses (GSEA) using hallmark gene‐sets revealed that the 10 most TLR2‐responsive pathways in high TLR2‐expressing human GC cells included ROS, p53, c‐Myc, JAK‐STAT3 and Kras signaling gene networks (Supporting Information Fig. S2C), which are also implicated in respiration, ROS production and cell metabolism . Collectively, these data suggest that the expression of SOD2 is strongly induced at the transcriptional level upon TLR2 activation in high TLR2‐expressing cancer cells, and is associated with enrichment of multiple metabolic or oxidative stress related genes.…”

Section: Resultsmentioning

confidence: 86%

“…S2C), which are also implicated in respiration, ROS production and cell metabolism. [20][21][22] Collectively, these data suggest that the expression of SOD2 is strongly induced at the transcriptional level upon TLR2 activation in high TLR2-expressing cancer cells, and is associated with enrichment of multiple metabolic or oxidative stress related genes.…”

Section: Sod2 Is Strongly Induced Upon Tlr2 Activation In Human Gc Cellsmentioning

confidence: 79%

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Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Liu

Ying

et al. 2019

Intl Journal of Cancer

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Toll‐like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial‐ and host‐derived components, and their dysregulation is a common feature of various inflammation‐associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand‐induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray‐based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene‐sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese‐dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK‐STAT3, JNK MAPK and NF‐κB. Furthermore, siRNA‐mediated suppression of SOD2 ameliorated the TLR2‐induced metabolic shift in human GC cancer cells. Importantly, patient‐derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2‐SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2‐SOD2 axis as a potential biomarker for therapy and prognosis in cancer.

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Section: Resultsmentioning

confidence: 86%

Section: Sod2 Is Strongly Induced Upon Tlr2 Activation In Human Gc Cellsmentioning

confidence: 79%

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Liu

Ying

et al. 2019

Intl Journal of Cancer

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“…Reactive oxygen species (ROS), such as superoxide anion radicals, hydroxyl radicals, and hydrogen peroxide, are natural by‐products of aerobic metabolism . In cells, mitochondria are the primary source of endogenous intracellular reactive species.…”

Section: Oxidative Stressmentioning

confidence: 99%

Therapeutic targeting of cellular stress responses in cancer

Chen

Xie

2018

Thoracic Cancer

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Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA‐damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy.

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“…Impaired OxPhos together with compensatory fermentation leads to the accumulation of reactive oxygen species (ROS) (85)(86)(87). ROS are carcinogenic and mutagenic, and are largely responsible for the genomic instability and mutations seen in tumor cells (85,(87)(88)(89)(90)(91)(92)(93). In other words, the mutations seen in tumor cells arise as a consequence of impaired energy metabolism (32,64).…”

Section: Role Of Reactive Oxygen Species (Ros) and Oncogenes In The Omentioning

confidence: 99%

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

et al. 2020

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Breast cancer remains as a significant cause of morbidity and mortality in women. Ultrastructural and biochemical evidence from breast biopsy tissue and cancer cells shows mitochondrial abnormalities that are incompatible with energy production through oxidative phosphorylation (OxPhos). Consequently, breast cancer, like most cancers, will become more reliant on substrate level phosphorylation (fermentation) than on oxidative phosphorylation (OxPhos) for growth consistent with the mitochondrial metabolic theory of cancer. Glucose and glutamine are the prime fermentable fuels that underlie therapy resistance and drive breast cancer growth through substrate level phosphorylation (SLP) in both the cytoplasm (Warburg effect) and the mitochondria (Q-effect), respectively. Emerging evidence indicates that ketogenic metabolic therapy (KMT) can reduce glucose availability to tumor cells while simultaneously elevating ketone bodies, a non-fermentable metabolic fuel. It is suggested that KMT would be most effective when used together with glutamine targeting. Information is reviewed for suggesting how KMT could reduce systemic inflammation and target tumor cells without causing damage to normal cells. Implementation of KMT in the clinic could improve progression free and overall survival for patients with breast cancer.

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Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

Cited by 152 publications

References 122 publications

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

Therapeutic targeting of cellular stress responses in cancer

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

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