A Somatic Mutation of the KEAP1 Gene in Malignant Melanoma Is Involved in Aberrant NRF2 Activation and an Increase in Intrinsic Drug Resistance

Miura, Shunsuke; Shibazaki, Masahiko; Kasai, Shuya; Yasuhira, Shinji; Watanabe, Ayano; Inoue, Tsuyoshi; Kageshita, Yuich; Tsunoda, Kenji; Takahashi, Kazuhiro; Akasaka, Toshihide; Masuda, Tomoyuki; Maesawa, Chihaya

doi:10.1038/jid.2013.343

Cited by 32 publications

(27 citation statements)

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“…Although p53 is a key tumor suppressor, the p53 target gene TIGAR has been demonstrated to possess both an antioxidant function and serve as an oncogene in intestinal cancer (37). Regulation of the antioxidant regulator Nrf2 by Sesn2 may also play a role in the oncogenic function of Sesn2 (7), as the antioxidant Nrf2 is shown to be an oncogene in pancreatic cancer (38) and is implicated as an oncogene in melanoma and SCC (39,40). Inhibition of Nrf2 by Brusatol enhances the efficacy of chemotherapy (41).…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Zhao

Shah

Budanov

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Zhao

Shah

Budanov

et al. 2014

Journal of Biological Chemistry

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“…A previous study revealed that several melanoma cell lines have detectable endogenous expression of NQO1 (21 which results in NRF2 stabilization (22). On the basis of these findings, we hypothesized that certain melanoma cells may be constitutionally sensitive to NQO1-dependent antitumor drugs, including β-lap, and that this sensitivity may be further increased through activation of the KEAP1-NRF2 axis.…”

Section: Introductionmentioning

confidence: 90%

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

et al. 2017

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Abstract. NAD(P)H quinone oxidoreductase 1 (NQO1)-dependent antitumor drugs such as β-lapachone (β-lap) are attractive candidates for cancer chemotherapy because several tumors exhibit higher expression of NQO1 than adjacent tissues. Although the association between NQO1 and β-lap has been elucidated, the effects of a NQO1-inducer and β-lap used in combination remain to be clarified. It has previously been reported that melanoma cell lines have detectable levels of NQO1 expression and are sensitive to NQO1-dependent drugs such as 17-allylamino-17-demethoxygeldanamycin. The present study was conducted to investigate the involvement of NQO1 in β-lap-mediated toxicity and the utility of combination treatment with a NQO1-inducer and β-lap in malignant melanoma cell lines. Decreased expression or inhibition of NQO1 caused these cell lines to become less sensitive to β-lap, indicating a requirement of NQO1 activity for β-lap-mediated toxicity. Of note was that carnosic acid (CA), a compound extracted from rosemary, was able to induce further expression of NQO1 through NF-E2 related factor 2 (NRF2) stabilization, thus significantly enhancing the cytotoxicity of β-lap in all of the melanoma cell lines tested. Taken together, the data presented in the current study indicated that the NRF2-NQO1 axis may have potential value as a therapeutic target in malignant melanoma to improve the rate of clinical response to NQO1-dependent antitumor drugs. IntroductionMalignant melanoma is one of the most aggressive forms of cancer, exhibiting resistance to various forms of chemotherapy.The global incidence and mortality rates of malignant melanoma are increasing (1-3). Novel targeted therapies designed to kill melanoma cells harboring mutations in B-Raf proto-oncogene, serine/threonine kinase (BRAF) have been developed using vemurafenib, which is a specific BRAF inhibitor (4,5). Missense mutations to the BRAF gene, most commonly a valine-to-glutamic acid substitution at codon 600, has been observed in ~80% of melanocytic nevi and ~50% of melanomas (6-9). In addition to this BRAF mutation, another therapeutic target has been investigated, as melanomas, including acral lentiginous melanoma, the most common type in ethnicities that produce high levels of melanin, have a low frequency of BRAF gene mutation (10,11). However, details of the mechanism responsible for the drug insensitivity of melanomas lacking BRAF mutations have been largely unclear. On the basis of the aforementioned background, a search for novel therapeutic strategies is justified.β-lapachone (β-lap), a lipophilic cytotoxic o-naphtoquinone derived from the bark of the South American Lapacho tree (Tabebuia avellanedae), has recently attracted attention as an antitumor drug (12,13). The mechanism of its antitumor effect is considered to involve the formation of reactive oxygen species (ROS) (13-15). ROS and other types of radicals are involved in a variety of biological phenomena, including tumorigenesis, degenerative disease and aging (16,17), and are also important medi...

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“…Somatic mutations in Nrf2 or its negative regulators (Keap1 and Cul3) have been shown to be responsible for the high levels of Nrf2 in certain tumors, such as lung cancer, melanoma, renal clear cell carcinoma, and hepatocellular carcinoma [53–57]. High levels of Nrf2 in these cancer cells provide a cellular environment conducive to growth and survival under detrimental conditions.…”

Section: The Pathological Consequences Of Prolonged Nrf2 Activatiomentioning

confidence: 99%

p62 links autophagy and Nrf2 signaling

Jiang

Harder

Vega

et al. 2015

Free Radical Biology and Medicine

514

345

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The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation.

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A Somatic Mutation of the KEAP1 Gene in Malignant Melanoma Is Involved in Aberrant NRF2 Activation and an Increase in Intrinsic Drug Resistance

Cited by 32 publications

References 14 publications

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Sestrin2 Protein Positively Regulates AKT Enzyme Signaling and Survival in Human Squamous Cell Carcinoma and Melanoma Cells

Carnosic acid, an inducer of NAD(P)H quinone oxidoreductase 1, enhances the cytotoxicity of β‑lapachone in melanoma cell lines

p62 links autophagy and Nrf2 signaling

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