Selective Induction of Tumor Cell Apoptosis by a Novel P450-mediated Reactive Oxygen Species (ROS) Inducer Methyl 3-(4-Nitrophenyl) Propiolate

Sun, Xiaoxiao; Ai, Midan; Wang, Ying; Shen, Shensi; Gu, Yuan; Jin, Yi; Zhou, Zuyu; Long, Ya‐Qiu; Yu, Qiang

doi:10.1074/jbc.m112.429316

Cited by 46 publications

(37 citation statements)

References 51 publications

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“…S7E), these data revealed that CYP3A5-induced intracellular ROS accumulation may play the key factor for the regulation of mTORC2-ribosome interaction, mTORC2 kinase activity, and mTORC2/p-AKT (S473) signaling. As an important supporting evidence, the GSH/GSSG ratio, which are negatively correlated with ROS level (16)(17)(18), in clinical HCC samples (n ¼ 62, 31 with microvascular invasion named as HM tissues, 31 without microvascular invasion named as LM tissues) were measured and found the remarkably lower GSH/GSSG level in the LM group (Fig. 6H).…”

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

“…These mono-oxygenase reactions depend on electron transfer from NADPH via FAD adrenodoxin reductase and 2Fe-2S adrenodoxin (16)(17)(18). These systems can function as a futile NADPH oxidase, oxidizing NADPH in absence of substrate, and leak electrons via adrenodoxin and P450 to O 2 , producing superoxide and other ROS (16)(17)(18).…”

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

“…Rictor controls the stability of the mTORC2 complex (14,32). mTORC2 is primarily activated by growth factors despite its underlying mechanism remaining largely unknown (16). AKT is an important kinase mediating survival signaling, which is regulated by phosphorylation on Thr308 by PDK1 and on Ser473 by several other kinases, as well as mTORC2 (33).…”

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

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CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

et al. 2015

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CYP3A5 is a cytochrome P450 protein that functions in the liver metabolism of many carcinogens and cancer drugs. However, it has not been thought to directly affect cancer progression. In this study, we challenge this perspective by demonstrating that CYP3A5 is downregulated in many hepatocellular carcinomas (HCC), where it has an important role as a tumor suppressor that antagonizes the malignant phenotype. CYP3A5 was downregulated in multiple cohorts of human HCC examined. Lower CYP3A5 levels were associated with more aggressive vascular invasion, poor differentiation, shorter time to disease recurrence after treatment, and worse overall patient survival. Mechanistic investigations showed that CYP3A5 overexpression limited MMP2/9 function and suppressed HCC migration and invasion in vitro and in vivo by inhibiting AKT signaling. Notably, AKT phosphorylation at Ser473 was inhibited in CYP3A5-overexpressing HCC cells, an event requiring mTORC2 but not Rictor/mTOR complex formation. CYP3A5-induced ROS accumulation was found to be a critical upstream regulator of mTORC2 activity, consistent with evidence of reduced GSH redox activity in most clinical HCC specimens with reduced metastatic capacity. Taken together, our results defined CYP3A5 as a suppressor of HCC pathogenesis and metastasis with potential utility a prognostic biomarker. Cancer Res; 75(7); 1470-81. Ó2015 AACR.

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Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

Section: Cyp3a5-induced Intracellular Ros Enrichment Is Responsible Fmentioning

confidence: 99%

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CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

et al. 2015

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“…AFs form after a series of highly organized oxidation-reduction reactions. Several studies provided evidences indicating that CYP450 enzymes generate superoxide hydrogen peroxide (H 2 O 2 ) as intermediate compounds, and these ROS can cause apoptosis and other cell pathologies [45][46][47]. AFB1 is able to induce ROS generation, which causes oxidative stress.…”

Section: Efects On Oxidative Stress Of Alatoxinmentioning

confidence: 99%

“…The oxidative stress caused by AFB1 may be one of the underlining mechanisms for AFB1-induced cell injury and DNA damage, which eventually lead to tumorigenesis [37]. Studies have revealed that AFB1 alters cell cycle and apoptosis-signaling pathways in liver cell models [43,47,51,52]. AFB1 can cause an increase in ROS formation in animals' target organs including rat liver, duck liver, and mouse lung [37,44,53].…”

Section: Efects On Oxidative Stress Of Alatoxinmentioning

confidence: 99%

The Effect on Oxidative Stress of Aflatoxin and Protective Effect of Lycopene on Aflatoxin Damage

Yılmaz¹,

Kaya²,

Kisaçam³

2017

Aflatoxin-Control, Analysis, Detection and Health Risks

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Alatoxin (AF) is polysubstituted bifuranocoumarins that are secondary fungal metabolites produced by parasiticus/lavus group of the genus Aspergillus. AF is hepatotoxic, nephrotoxic, mutagenic, teratogenic, genotoxic, and immunotoxic, so the International Agency for Research on Cancer has classiied AF as class I human carcinogen. AF-mediated cell injury may be associated with the release of free radicals, and these radicals initiate lipid peroxidation and a damaging process in biological systems since all cell membranes contain the polyunsaturated faty acids (PUFAs), which are substrates for such a reaction. One of the causes for AF-induced toxicity is the oxidative stress, which leads to the improved generation of reactive oxygen species (ROS) and the oxidative DNA damage. Lycopene, a naturally occurring carotenoid, has drawn a particular atention in recent years because of its high antioxidant activity and free radical scavenging capacity and has been shown to be efective against oxidative stress due to AF. Lycopene blocks Phase 1 metabolic enzymes of AFB such as 3A4, 2A6, and 1A2.

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

Rodic

Vincent

2017

Intl Journal of Cancer

152

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Cancer cells exhibit a wide range of metabolic phenotypes, ranging from strict aerobic glycolysis to increased mitochondrial respiration. The cause and utility of this metabolic variation is poorly understood. Given that cancer cells experience heavy selection within their microenvironment, survival requires metabolic adaptation to both extracellular and intracellular conditions. Herein, we suggest that reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype. Intracellular ROS levels can be modified by an assortment of critical parameters including oxygenation, glucose availability and growth factors. ROS act as integrators of environmental information as well as downstream effectors of signaling pathways. Maintaining ROS within a narrow range allows malignant cells to enhance growth and invasion while limiting their apoptotic susceptibility. Cancer cells actively modify their metabolism to optimize intracellular ROS levels and thereby improve survival. Furthermore, we highlight distinct metabolic phenotypes in response to oxidative stress and their tumorigenic drivers.

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Selective Induction of Tumor Cell Apoptosis by a Novel P450-mediated Reactive Oxygen Species (ROS) Inducer Methyl 3-(4-Nitrophenyl) Propiolate

Cited by 46 publications

References 51 publications

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

CYP3A5 Functions as a Tumor Suppressor in Hepatocellular Carcinoma by Regulating mTORC2/Akt Signaling

The Effect on Oxidative Stress of Aflatoxin and Protective Effect of Lycopene on Aflatoxin Damage

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

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