Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer

Homma, Shinsuke; Ishii, Yukio; Morishima, Yuko; Yamadori, Tadahiro; Matsuno, Yosuke; Haraguchi, Norihiro; Kikuchi, Norihiro; Satoh, Hiroaki; Sakamoto, Tohru; Hizawa, Nobuyuki; Itoh, Ken; Yamamoto, Masayuki

doi:10.1158/1078-0432.ccr-08-2822

Cited by 384 publications

(343 citation statements)

References 35 publications

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“…Because of these potential negative roles of Nrf2 signaling in chemotherapy, suppression of Nrf2/ARE activity during cancer treatment could be clinically beneficial (Kensler and Wakabayashi, 2010). The A549 cells used in the present study are known to have constitutively activated Nrf2 signaling (Homma et al, 2009). We also demonstrated higher Nrf2 signaling activity in these cells than in HEK293 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

Lim

Lee

Cho

et al. 2013

Molecules and Cells

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti-cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling.

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Section: Discussionmentioning

confidence: 99%

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

Lim

Lee

Cho

et al. 2013

Molecules and Cells

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“…It is well known that several therapeutic strategies, for example anticancer radiotherapy and chemotherapy, largely depend on ROS manipulation to induce cytotoxicity. More recently, there is a growing body of evidence implicating NRF2 and ROS in the promotion of cellular proliferation and therapeutic resistance in cancer cells [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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“…For instance, suppression of endogenous Nrf2, either by transfecting Nrf2-siRNA or overexpressing Keap1, sensitized cancer cells to chemotherapeutic drugs. Conversely, overexpression of Nrf2 in cancer cells that have low basal levels of Nrf2, enhanced resistance in a variety of cancer cells including neuroblastoma, breast, ovarian, prostate, lung, and pancreatic cancer cells (28)(29)(30)(31)(32). Combined use of Nrf2-siRNA and carboplatin inhibited the growth of A549 xenografts in mice (33).…”

mentioning

confidence: 99%

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

Ren

Villeneuve

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

565

506

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The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

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Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer

Cited by 384 publications

References 35 publications

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

4-Methoxychalcone Enhances Cisplatin-Induced Oxidative Stress and Cytotoxicity by Inhibiting the Nrf2/ARE-Mediated Defense Mechanism in A549 Lung Cancer Cells

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

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