Genetic Alteration of Keap1 Confers Constitutive Nrf2 Activation and Resistance to Chemotherapy in Gallbladder Cancer

Shibata, Tatsuhiro; Kokubu, Akiko; Gotoh, Masahiro; Ojima, Hidenori; Ohta, Tsutomu; Yamamoto, Masayuki; Hirohashi, Setsuo

doi:10.1053/j.gastro.2008.06.082

Cited by 436 publications

(381 citation statements)

References 35 publications

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“…Several studies have suggested that the beneficial effects of chemopreventive drugs on the suppression of carcinogenesis are mediated through activation of NRF2 (86). In contrast, some studies suggest an oncogenic characteristic of NRF2 causing constitutive activation and resistance to chemotherapy (87). Just a transient (and not a permanent) activation of NRF2 by non-thermal plasma should not be associated with cancer formation.…”

Section: Discussionmentioning

confidence: 99%

Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways

Schmidt

Dietrich

Steuer

et al. 2015

Journal of Biological Chemistry

129

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Background: Non-thermal plasma provides an interesting therapeutic opportunity to control redox-based processes, e.g. wound healing. Results: The transcription factor NRF2 and downstream signaling molecules were found to act as key controllers orchestrating the cellular response. Conclusions: Plasma triggers hormesis-like processes in keratinocytes. Significance: These findings facilitate the understanding of plasma-tissue interaction and its deduced clinical application.

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Section: Discussionmentioning

confidence: 99%

Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways

Schmidt

Dietrich

Steuer

et al. 2015

Journal of Biological Chemistry

129

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“…[6][7][8][13][14][15][16][17][18][19][20] Lower frequencies of mutations were demonstrated in endometrioid endometrial tumors (8.5%), non-clear cell ovarian cancer (8%), hepatocellular carcinoma (8.9%), colorectal cancer (7.8%), biliary duct carcinomas (5%), breast cancer (2%), prostate cancer (1.3%) and gastric cancer (1%). 13,17,21,22 However, immunohistochemical studies in lung cancer, endometrial tumors, renal and breast cancer demonstrated a high frequency of KEAP1 downregulation and/or Nrf2 overexpression in these tumor types, suggesting that the deregulation of KEAP1 may play a role in carcinogenesis beside the presence of genomic alterations. 19,[23][24][25] We have recently confirmed that epigenetic modification by promoter methylation is a main mechanism of regulation of KEAP1 gene expression.…”

Section: Patients and Treatmentmentioning

confidence: 99%

AberrantKeap1methylation in breast cancer and association with clinicopathological features

et al. 2013

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“…In addition to lung cancer, overexpression of Nrf2 has been shown in several other cancers. For example, Nrf2 expression was increased in 91.5% of cancer tissues from head and neck squamous cell carcinoma (HNSCC) (23), and the frequency of Keap1 mutation was 30.7% (4 out of 13) in gallbladder cancer samples (24). By the same token, mutations in Nrf2 can disrupt Keap1-dependent repression and result in overexpression of Nrf2.…”

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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Genetic Alteration of Keap1 Confers Constitutive Nrf2 Activation and Resistance to Chemotherapy in Gallbladder Cancer

Cited by 436 publications

References 35 publications

Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways

Non-thermal Plasma Activates Human Keratinocytes by Stimulation of Antioxidant and Phase II Pathways

AberrantKeap1methylation in breast cancer and association with clinicopathological features

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

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