Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
Compound
Query: EC:1.6.5.2 (
NQO1
)
6,196
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The NAD(P)H:quinone oxidoreductase 1 (
NQO1
) is a phase II enzyme that reduces and detoxifies quinones and their derivatives. Although overexpressed in tumor cells, the
NQO1
has been linked with the suppression of carcinogenesis, and the effect of
NQO1
on tumor necrosis factor (TNF), a cytokine that mediates tumorigenesis through proliferation, invasion, angiogenesis, and metastasis of tumors, is currently unknown. The purpose of our study was to determine the role of
NQO1
in TNF cell signaling by using keratinocytes derived from wild-type and
NQO1
gene-deleted mice. TNF induced nuclear factor (NF)-kappaB activation in wild-type but not in
NQO1
-deleted cells. The treatment of wild-type cells with dicoumarol, a known inhibitor of
NQO1
, also abolished TNF-induced NF-kappaB activation. NF-kappaB activation induced by lipopolysaccharide, phorbol ester, and cigarette smoke, was also abolished in
NQO1
-deleted cells. The suppression of NF-kappaB activation was mediated through the inhibition of IkappaBalpha kinase activation, IkappaBalpha phosphorylation, and IkappaBalpha degradation. Further, the deletion of
NQO1
abolished TNF-induced c-Jun N-terminal kinase, Akt, p38, and
p44
/p42 mitogen-activated protein kinase activation. TNF also induced the expression of various NF-kappaB-regulated gene products involved in cell proliferation, antiapoptosis, and invasion in wild-type
NQO1
keratinocytes but not in
NQO1
-deleted cells. The suppression of these antiapoptotic gene products increased TNF-induced apoptosis in
NQO1
-deleted cells. We also found that TNF activated
NQO1
, and
NQO1
-specific small interfering RNA abolished the TNF-induced
NQO1
activity and NF-kappaB activation. Overall, our results indicate that
NQO1
plays a pivotal role in signaling activated by TNF and other inflammatory stimuli and that its suppression is a potential therapeutic strategy to inhibit the proliferation, survival, invasion, and metastasis of tumor cells.
...
PMID:Genetic deletion of NAD(P)H:quinone oxidoreductase 1 abrogates activation of nuclear factor-kappaB, IkappaBalpha kinase, c-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis. 1668 9
NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that catalyzes the two-electron reduction of quinones and quinoid compounds to hydroquinones. Although the role of a homologue, NAD(P)H:quinone oxidoreductase 1 (
NQO1
), is well defined in oxidative stress, neoplasia, and carcinogenesis, little is known about the mechanism of actions of NQO2 in these cellular responses. Whether NQO2 has any role in tumor necrosis factor (TNF) signaling was investigated using keratinocytes derived from wild-type and NQO2 knockout (NQO2-/-) mice. Although exposure of wild-type cells to TNF led to activation of nuclear factor-kappaB (NF-kappaB) and IkappaBalpha kinase, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation, this cytokine had no effect on NQO2-/- cells. Deletion of NQO2 also abolished TNF-induced c-Jun NH2-terminal kinase, Akt, p38, and
p44
/p42 mitogen-activated protein kinase activation. The induction of various antiapoptotic gene products (MMP-9, cyclin D1, COX-2, IAP1, IAP2, Bcl-2, cFLIP, and XIAP) by TNF was also abolished in NQO2-/- cells. This correlated with potentiation of TNF-induced apoptosis as indicated by cell viability, Annexin V staining, and caspase activation. In agreement with this, we also found that TNF activated NQO2, and NQO2-specific small interfering RNA abrogated the TNF-induced NQO2 activity and NF-kappaB activation. Overall, our results indicate that deletion of NQO2 plays a differential role in TNF signaling pathway: by suppressing cell survival signals and potentiating TNF-induced apoptosis.
...
PMID:Deficiency of NRH:quinone oxidoreductase 2 differentially regulates TNF signaling in keratinocytes: up-regulation of apoptosis correlates with down-regulation of cell survival kinases. 1794 34
Oxidative stress-induced damage to the retinal pigmented epithelium (RPE), a specialised post-mitotic monolayer that maintains retinal homeostasis, contributes to the development of age-related macular degeneration (AMD). Curcumin (Cur), a naturally occurring antioxidant, was previously shown to have the ability to protect RPE cells from oxidative stress. However, poor solubility and bioavailability makes Cur a poor therapeutic agent. As prodrug approaches can mitigate these limitations, we compared the protective properties of the Cur prodrug curcumin diethyl disuccinate (CurDD) against Cur in relation to oxidative stress induced in human ARPE-19 cells. Both CurDD and Cur significantly decreased H
2
O
2
-induced reactive oxygen species (ROS) production and protected RPE cells from oxidative stress-induced death. Both drugs exerted their protective effects through the modulation of
p44
/42 (ERK) and the involvement of downstream molecules Bax and Bcl-2. Additionally, the expression of antioxidant enzymes HO-1 and
NQO1
was also enhanced in cells treated with CurDD and Cur. In all cases, CurDD was more effective than its parent drug against oxidative stress-induced damage to ARPE-19 cells. These findings highlight CurDD as a more potent drug compared to Cur against oxidative stress and indicate that its protective effects are exerted through modulation of key apoptotic and antioxidant molecular pathways.
...
PMID:Protective Effects of Curcumin Ester Prodrug, Curcumin Diethyl Disuccinate against H
2
O
2
-Induced Oxidative Stress in Human Retinal Pigment Epithelial Cells: Potential Therapeutic Avenues for Age-Related Macular Degeneration. 3132 99
