NQO1 is Required for Beta-lapachone-mediated Downregulation of Breast Cancer Stem Cell Activity

Kim, Dong Wook; Cho, Je‐Yoel

doi:10.20944/preprints201810.0719.v1

2018

DOI: 10.20944/preprints201810.0719.v1

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NQO1 is Required for Beta-lapachone-mediated Downregulation of Breast Cancer Stem Cell Activity

Dong Wook Kim¹,

Je‐Yoel Cho²

Abstract: Background: Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. beta-lapachone (bL) has been widely used to treat cancer development, but its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast cancer stem cell (BCSC) marker positive cells, MDA-MB-231. Methods:… Show more

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Cited by 5 publications

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“…β-lapachone increases NAD(+)/NADH ratio in kidney and decreases the renal levels of nuclear p-NF-κB and its correspondent downstream effectors TNF-α, IL-1β, IL-6, and iNOS to play a protective role against DOX-induced nephrotoxicity in mice (8). In addition, recent studies have shown that the anticancer effects of β-lapachone are performed through the inhibition of type II topoisomerase, activation of NAD(P)H: Quinone oxidoreductase I and induction of oxidative stress in numerous cancers (9)(10)(11)(12)(13).…”

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Peroxiredoxin V Reduces β-Lapachone-induced Apoptosis of Colon Cancer Cells

et al. 2019

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Background/Aim: Peroxiredoxin (Prx) V has been known as an antioxidant enzyme which scavenges intracellular reactive oxygen species (ROS). Also, Prx V has been shown to mediate cell apoptosis in various cancers. However, the mechanism of Prx V-induced apoptosis in colon cancer cells remains unknown. Thus, in this study we analyzed the effects of Prx V in β-lapachone-induced apoptosis in SW480 human colon cancer cells. Materials and Methods: β-lapachoneinduced apoptosis was analyzed by the MTT assay, western blotting, fluorescence microscopy, Annexin V staining and flow cytometry. Results: Overexpression of Prx V, significantly decreased β-lapachone-induced cellular apoptosis and Prx V silencing increased β-lapachone-induced cellular apoptosis via modulating ROS scavenging activity compared to mock SW480 cells. In addition, to further explore the mechanism of Prx V regulated β-lapachone-induced SW480 cells apoptosis, the Wnt/β-catenin signaling was studied. The Wnt/ β-catenin signaling pathway was found to be induced by β-lapachone. Conclusion: Prx V regulates SW480 cell apoptosis via scavenging ROS cellular levels and mediating the Wnt/βcatenin signaling pathway, which was induced by β-lapachone.Colon cancer is the third most common cancer, and the fourth most common cause of cancer-related mortality worldwide (1, 2). According to the statistics of World Health Organization (WHO), 1.36 million new colon cancer cases and 0.69 million deaths have been reported worldwide in 2014.The survival rate of advanced colon cancer is very low. As American Cancer Society has reported, the 5-year survival rates of stage III and stage IV colon cancer are 53% and 11%, respectively (3). Therefore, a clear understanding of the underlying molecular mechanisms of colon cancer is necessary for the development of successful early diagnostic strategies and therapeutic management of colon cancer. Thus, we focused on the mechanism of action of the antioxidant enzyme system in colon cancer cells.Members of the peroxiredoxin (Prx) family, a family of antioxidant enzymes, have been reported to maintain the redox balance in cells by functioning as reactive oxygen species (ROS) scavengers. These members are capable of converting H 2 O 2 to H 2 O and mediating signal transduction in mammalian cells (4). Among the family members, Prx V is the fifth subfamily of peroxiredoxins, has atypical 2-Cys and is widely distributed in the cytoplasm and mitochondria (5). It has been reported that the expression of Prx V is positively correlated with radio-resistance in 3677

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Peroxiredoxin V Reduces β-Lapachone-induced Apoptosis of Colon Cancer Cells

et al. 2019

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A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells

Monroy-Cárdenas,

Andrades,

Almarza

et al. 2023

Antioxidants

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Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV–1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV–1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV–1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV–1 is a NOQ1 substrate. Importantly, FRV–1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV–1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.

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Measuring NQO1 Bioactivation Using [2H7]Glucose

Mahar

Chang

Merritt

2021

Cancers

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Treatment of cancers with β-lapachone causes NAD(P)H: quinone oxidoreductase 1 (NQO1) to generate an unstable hydroquinone that regenerates itself in a futile cycle while producing reactive oxygen species (ROS) in the form of superoxide and subsequently hydrogen peroxide. Rapid accumulation of ROS damages DNA, hyperactivates poly-ADP-ribose polymerase-I, causes massive depletion of NAD+/ATP, and hampers glycolysis. Cells overexpressing NQO1 subsequently die rapidly through an NAD+-keresis mechanism. Assessing changes in glycolytic rates caused by NQO1 bioactivation would provide a means of assessing treatment efficacy, potentially lowering the chemotherapeutic dosage, and reducing off-target toxicities. NQO1-mediated changes in glycolytic flux were readily detected in A549 (lung), MiaPaCa2 (pancreatic), and HCT-116 (colon) cancer cell lines by 2H-NMR after administration of [2H7]glucose. The deuterated metabolic products 2H-lactate and HDO were quantified, and linear relationships with glucose consumption for both products were observed. The higher concentration of HDO compared to 2H-lactate allows for more sensitive measurement of the glycolytic flux in cancer. Gas chromatography-mass spectrometry analysis agreed with the NMR results and confirmed downregulated energy metabolism in NQO1+ cells after β-lapachone treatment. The demonstrated method is ideal for measuring glycolytic rates, the effects of chemotherapeutics that target glycolysis, and has the potential for in vivo translation.

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NQO1 is Required for Beta-lapachone-mediated Downregulation of Breast Cancer Stem Cell Activity

Cited by 5 publications

References 50 publications

Peroxiredoxin V Reduces β-Lapachone-induced Apoptosis of Colon Cancer Cells

Peroxiredoxin V Reduces β-Lapachone-induced Apoptosis of Colon Cancer Cells

A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells

Measuring NQO1 Bioactivation Using [2H7]Glucose

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