Regulation of redox balance in cancer and T cells

Kong, Hyewon; Chandel, Navdeep S.

doi:10.1074/jbc.tm117.000257

Cited by 128 publications

(100 citation statements)

References 99 publications

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“…While low levels of ROS can promote tumorigenesis [62], at high levels they can also induce cell death [63,64]. Extensive reviews on the role of ROS in cancer can be read elsewhere [65][66][67]. Previous studies demonstrate a role for ROS scavenging in protecting cells against anoikis [68].…”

Section: Surviving Oxidative Changes In the Circulation And Distant Pmentioning

confidence: 99%

Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies

Pereira

Chio

2019

Genes

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Pancreatic ductal adenocarcinoma is an extremely aggressive disease with a high metastatic potential. Most patients are diagnosed with metastatic disease, at which the five-year survival rate is only 3%. A better understanding of the mechanisms that drive metastasis is imperative for the development of better therapeutic interventions. Here, we take the reader through our current knowledge of the parameters that support metastatic progression in pancreatic ductal adenocarcinoma, and the experimental models that are at our disposal to study this process. We also describe the advantages and limitations of these models to study the different aspects of metastatic dissemination.

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Section: Surviving Oxidative Changes In the Circulation And Distant Pmentioning

confidence: 99%

Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies

Pereira

Chio

2019

Genes

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“…At low levels, ROS are mutagenic and can promote tumor development by activating signaling pathways that regulate cellular survival, proliferation, differentiation, and metabolic adaptation. However, at high levels, ROS become toxic leading to oxidative stress and cell death or senescence (1,5).…”

Section: Introductionmentioning

confidence: 99%

“…To compensate for higher levels of intrinsic ROS, cancer cells have evolved adaptive mechanisms that increase their antioxidant capacity. NRF2 upregulation has been observed in multiple tumor types, and its expression has been shown to be required for pancreatic and lung cancer development (5)(6)(7). Thus, compared with normal cells, cancer cells with increased oxidative stress are likely more vulnerable to damage by further ROS insults, making modulation of tumor redox homeostasis an attractive therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

Bioactivation of Napabucasin Triggers Reactive Oxygen Species–Mediated Cancer Cell Death

Froeling

Swamynathan

Deschênes

et al. 2019

Clinical Cancer Research

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Purpose: Napabucasin (2-acetylfuro-1,4-naphthoquinone or BBI-608) is a small molecule currently being clinically evaluated in various cancer types. It has mostly been recognized for its ability to inhibit STAT3 signaling. However, based on its chemical structure, we hypothesized that napabucasin is a substrate for intracellular oxidoreductases and therefore may exert its anticancer effect through redox cycling, resulting in reactive oxygen species (ROS) production and cell death. Experimental Design: Binding of napabucasin to NAD(P) H:quinone oxidoreductase-1 (NQO1), and other oxidoreductases, was measured. Pancreatic cancer cell lines were treated with napabucasin, and cell survival, ROS generation, DNA damage, transcriptomic changes, and alterations in STAT3 activation were assayed in vitro and in vivo. Genetic knockout or pharmacologic inhibition with dicoumarol was used to evaluate the dependency on NQO1. Results: Napabucasin was found to bind with high affinity to NQO1 and to a lesser degree to cytochrome P450 oxidoreductase (POR). Treatment resulted in marked induction of ROS and DNA damage with an NQO1-and ROS-dependent decrease in STAT3 phosphorylation. Differential cytotoxic effects were observed, where NQO1-expressing cells generating cytotoxic levels of ROS at low napabucasin concentrations were more sensitive. Cells with low or no baseline NQO1 expression also produced ROS in response to napabucasin, albeit to a lesser extent, through the one-electron reductase POR. Conclusions: Napabucasin is bioactivated by NQO1, and to a lesser degree by POR, resulting in futile redox cycling and ROS generation. The increased ROS levels result in DNA damage and multiple intracellular changes, one of which is a reduction in STAT3 phosphorylation.

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“…) and hydroxyl radical (OH À ) plus nonradical molecules, such as hypochlorous acid and H 2 O 2 [3], which have been linked to oxidative injury due to their high reactivity potential against proteins, lipids and DNA [10].…”

mentioning

confidence: 99%

“…Exogenous factors that contribute to ROS production are pollutants, chemicals/drugs, radiation and heavy metals [12]. Redox homeostasis is attained by cautious regulation of both ROS formation and removal from the body system [10]. Maintenance of homeostasis and signalling event of redox require the significant regulation of synthesis and detoxification.…”

mentioning

confidence: 99%

Reactive Oxygen Species, Cellular Redox Homeostasis and Cancer

Mydin¹,

Okekpa²

2019

Homeostasis - An Integrated Vision

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Redox homeostasis is attained by the cautious regulation of both reactive oxygen species (ROS) formation and removal from the body system. A shift in ROS balance promotes oxidative injury and tumour development by inflicting damage to DNA and inducing inconsistencies in the genome. The sources of endogenous ROS in a cell include mETC, NOX, LOX, cytochrome P450 and XO. The exogenous risk factors of ROS are pollutants, chemicals/drugs, radiation and heavy metals. Oxidative phosphorylation in the mitochondria produces ROS with unpaired electrons. Superoxide anion is the major ROS produced in the human mitochondria. Bulk of the ROS generation in the mitochondria occurs at the electron transport chain as derivatives of respiration. Cancer cells sustain ROS production by suppressing the antioxidant-generation system. Balance between ROS production and subsequent detoxification is regulated by scavenging enzymes and antioxidant agents. Failure in sirtuin-3 (SIRT3), ATM and p53 activities elevates the intracellular levels of ROS. PKCα induces the expression of NOX (DUOX) during cancer development and the consequent increase in ROS production. The PI3K/AKT signalling pathway activates NOX with consequent ROS production and subsequent induction of instability in the genome, leading to cancer. In conclusion, the interruption of the redox pathways that regulate ROS and its redox signalling activities affects cell physiology and can ultimately result in abnormal signalling, uncontrolled oxidative impairment and tumorigenesis.

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Regulation of redox balance in cancer and T cells

Cited by 128 publications

References 99 publications

Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies

Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies

Bioactivation of Napabucasin Triggers Reactive Oxygen Species–Mediated Cancer Cell Death

Reactive Oxygen Species, Cellular Redox Homeostasis and Cancer

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