NQO1 expression correlates inversely with NFκB activation in human breast cancer

Jamshidi, Maral; Bártková, Jiřina; Greco, Dario; Tommiska, Johanna; Fagerholm, Rainer; Aittomäki, Kristiina; Mattson, Johanna; Villman, Kenneth; Vrtěl, Radek; Lukáš, Jiří; Heikkilä, Päivi; Blomqvist, Carl; Bártek, Jiří; Nevanlinna, Heli

doi:10.1007/s10549-011-1629-5

Cited by 22 publications

(12 citation statements)

References 54 publications

(52 reference statements)

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“…Recently, Jamshidi et al (2012) have immunolocalized NQO1 in breast carcinoma, but they did not detect a significant association between NQO1 immunoreactivity and overall survival of the patients. NQO1 has been viewed as a 'good' protein that protects humans from genotoxic damage (Siegel & Ross 2000, Cheng et al 2010.…”

Section: Discussionmentioning

confidence: 92%

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

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Nuclear factor erythroid 2-related factor 2 (NRF2 (NFE2L2)) is an important transcriptional activator involved in the cellular defense mechanisms against electrophilic and oxidative stress. Recent studies have demonstrated that the expression of NRF2 protein is upregulated in several human malignancies and is associated with worse prognosis in these patients. However, the pathological and clinical significance of NRF2 has remained largely unknown in breast cancer patients. Therefore, in this study, we immunolocalized NRF2 in 106 breast carcinoma cases. NRF2 immunoreactivity was mainly detected in the nucleus of the breast carcinoma cells and it was positive in 44% of the cases. NRF2 status was significantly associated with histological grade, Ki-67 labeling index, p62 immunoreactivity, and NAD(P) H:quinone oxidoreductase 1 (NQO1) immunoreactivity, and the results of multivariate analyses revealed that NRF2 status was an independent adverse prognostic factor for both recurrence and disease-free survival of the patients. Subsequent in vitro studies demonstrated that the expression of NRF2 significantly increased the proliferation activity of MCF7 and SK-BR-3 breast carcinoma cells. These results indicate that nuclear NRF2 protein plays important roles in the proliferation and/or progression of breast carcinoma, and nuclear NRF2 immunoreactivity is therefore considered a potent prognostic factor in breast cancer patients.

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Section: Discussionmentioning

confidence: 92%

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Onodera¹,

Motohashi²,

Takagi³

et al. 2013

Endocrine-Related Cancer

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“…Interrogation of expression of these factors may allow us to predict efficacious doses required for improved efficacy of NQO1 bioactivatable drugs, such as β-lap, DNQ and their derivatives. Since NQO1 levels are over-expressed in breast cancer versus adjacent normal tissue (11), and particularly in ER+ breast cancer patients (38), these data strongly indicate use of this agent against breast, as well as many other solid tumors that specially over-expressed NQO1. Monitoring NQO1/catalase ratios in tumor vs normal tissue will be essential for ‘personalized therapies’ using β-lap or other NQO1 bioactivatable drugs.…”

Section: Discussionmentioning

confidence: 99%

Catalase Abrogates β-Lapachone–Induced PARP1 Hyperactivation–Directed Programmed Necrosis in NQO1-Positive Breast Cancers

Bey

Reinicke

Srougi

et al. 2013

Molecular Cancer Therapeutics

104

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Improving patient outcome by personalized therapy involves a thorough understanding of an agent’s mechanism of action. β-Lapachone (clinical forms, Arq501/Arq761) has been developed to exploit dramatic cancer-specific elevations in the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase (NQO1). NQO1 is dramatically elevated in solid cancers, including primary and metastatic (e.g., triple-negative (ER-, PR-, Her2/Neu-)) breast cancers. To define cellular factors that influence the efficacy of β-lapachone using knowledge of its mechanism of action, we confirmed that NQO1 was required for lethality and mediated a futile redox cycle where ~120 moles of superoxide were formed per mole of β-lapachone in 5 min. β-Lapachone induced reactive oxygen species (ROS), stimulated DNA single strand break-dependent PARP1 hyperactivation, caused dramatic loss of essential nucleotides (NAD+/ATP) and elicited programmed necrosis in breast cancer cells. While PARP1 hyperactivation and NQO1 expression were major determinants of β-lapachone-induced lethality, alterations in catalase expression, including treatment with exogenous enzyme, caused marked cytoprotection. Thus, catalase is an important resistance factor, and highlights H2O2 as an obligate ROS for cell death from this agent. Exogenous superoxide dismutase (SOD) enhanced catalase-induced cytoprotection. β-Lapachone-induced cell death included AIF translocation from mitochondria to nuclei, TUNEL+ staining, atypical PARP1 cleavage, and GAPDH S-nitrosylation, which were abrogated by catalase. We predict that the ratio of NQO1:catalase activities in breast cancer versus associated normal tissue are likely to be the major determinants affecting the therapeutic window of β-lapachone and other NQO1 bioactivatable drugs.

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“…Several reports establish an inverse correlation between NQO1 and NF-κB activation (23). In addition to IKK-mediated regulation of IκB-NF-κB interaction, its crosstalk with other cell-signaling networks determine cell fate (24).…”

Section: Introductionmentioning

confidence: 99%

NQO1 Suppresses NF-κB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis

et al. 2014

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NADPH reductase NQO1 is needed to maintain a cellular pool of antioxidants and this enzyme may contribute to tumorigenesis, on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting where oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKK-α and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set up immune-associated transcripts associated with inflammation and tumorigenesis in cells where NQO1 was attenuated, with IL-8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Further, NQO1 inhibition increased migration including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and pro-inflammatory cytokine signaling in prostate cancer. Further, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function.

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NQO1 expression correlates inversely with NFκB activation in human breast cancer

Cited by 22 publications

References 54 publications

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

NRF2 immunolocalization in human breast cancer patients as a prognostic factor

Catalase Abrogates β-Lapachone–Induced PARP1 Hyperactivation–Directed Programmed Necrosis in NQO1-Positive Breast Cancers

NQO1 Suppresses NF-κB–p300 Interaction to Regulate Inflammatory Mediators Associated with Prostate Tumorigenesis

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