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cells, nrf, aldhh, cancer, pubmed, cell, article, atra, google, scholar, levels, aldh, fig, cas, csclike, aldhl, aldha, expression, properties, ovarian, high, stem, activation, protein, tumor, treatment, level, resistance, compared, csc, usa, breast, aldhhigh, formation, adr, experiments, central, signaling, growth, cscs, autophagy, drug, bcrp, activity, determined, acid, akrc, nature, dehydrogenase, nqo,

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nature portfolio privacy policy national research foundation balb/c-nu/nu mice advertising nature 445 nature 432 nature aldh-h-derived tumor growth opti-mem media reprints human colon-cancer-initiating cells aldh1-low doxorubicin-resistant cells aldh1a1-mediated development japan thermo fisher scientific mi-kyoung kwak aldh-h-derived tumors aldefluor-derived fluorescence intensity retinoic acid receptor-α63 beta-catenin-regulated aldh1a1 aldo-keto reductase 1c1 pan-histone deacetylase inhibitor aldehyde-dehydrogenase gene transfer pancreatic tumour-initiating cells 5 μg/μl oligo dt12–18 social media anchorage-independent growth ability aldehyde dehydrogenase 1a1 cell death dis drug-tolerant cancer cells p62-mediated autophagic degradation aldh1-mediated nrf2 activation nrf2-mediated drug resistance real-time reverse transcriptase 5 μg/ml bovine insulin stable transgene-expressing cells aldh1-mediated nrf2 upregulation cd44-high colorectal cscs inhibits tumour formation sirna-mediated p62-silencing stem/progenitor cell properties aldh1-enriched ovarian cscs bo-hyun choi nrf2-mediated stress resistance c-met/pi3k signaling aldh1-high cancer cells sphere-forming capacity compared real-time rt-pcr student−newman−keuls tests

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• Oxidative stress, mammospheres and Nrf2–new implication for breast cancer therapy?
• Stem cells in cancer: instigators and propagators?
• Tackling the cancer stem cells—what challenges do they pose?

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         description:Aldehyde dehydrogenase 1A1 (ALDH1A1) is one of cancer stem cell (CSC) markers, and high ALDH1 expression has been related to drug resistance and facilitated tumor growth. In this study, we investigated the potential involvement of nuclear factor erythroid 2-like 2 (NFE2L2/NRF2) in CSC-like properties of ALDH-high ovarian CSCs. Our experimental system, ALDH1A1-high (ALDH-H) subpopulation, was isolated and stabilized using doxorubicin-resistant ovarian cancer A2780 cells. ALDH-H exerted CSC-like properties such as drug resistance, colony/sphere formation, and enhanced tumor growth along with high levels of CSCs markers compared to ALDH1A1-low (ALDH-L). Levels of NRF2 and subsequent target genes substantially increased in ALDH-H cells, and the increase in ALDH1A1 and p62 was associated with NRF2 upregulation. ALDH1A1-silencing blocked increases in NRF2, drug efflux transporters, and p62, along with CSC markers in ALDH-H cells. The inhibition of p62, which was elevated in ALDH-H, suppressed NRF2 activation. High NRF2 level was confirmed in the ALDH1-high subpopulation from colon cancer HCT116 cells. The functional implication of NRF2 activation in ovarian CSCs was verified by two experimental approaches. First, CSC-like properties such as high CSC markers, chemoresistance, colony/sphere formation, and tumor growth were significantly inhibited by NRF2-silencing in ALDH-H cells. Second, all-trans retinoic acid (ATRA) suppressed ALDH1 expression, inhibiting NRF2 activation, which led to the attenuation of CSC-like properties in ALDH-H cells but not in ALDH-L cells. These results provide insight into the molecular basis of the ALDH1A1-mediated development of CSC-like properties such as stress/treatment resistance, and further suggest the therapeutic potential of ATRA in ALDH-high ovarian CSCs.
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