Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656116
Title: Targeting Nrf2 in inflammation and cancer
Author: Cowan, Jonathan
ISNI:       0000 0004 5346 9830
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2014
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Abstract:
The transcription factor Nrf2 protects against cellular stress by inducing cytoprotective proteins. Activation of Nrf2 protects against inflammation and oxidative damage in disease models in vitro and in vivo. Nrf2 activation may be a good therapeutic strategy in these diseases. Some dietary components activate Nrf2, which may be partially responsible for their beneficial effects in preventing disease. In this study a novel organosulfur compound from garlic, diallyl pentasulfide (DAPS), was investigated. DAPS strongly activated the Nrf2 pathway. Furthermore, it was a much more powerful activator of heme oxygenase-1 than any diallyl sulfides reported to date. Nrf2 is regulated by Keap1, which targets it for degradation. Disruption of the Nrf2/Keap1 interaction results in Nrf2 activation. In this study, a novel cell-penetrating peptide, based on the Keap1-binding site of Nrf2, disrupted the Nrf2/Keap1 interaction, and activated the Nrf2 pathway. Furthermore, it demonstrated anti-inflammatory activity, significantly inhibiting LPS-induced TNF expression in THP-1 monocytes, suggesting that the interaction is a valid therapeutic target in inflammation. In cancer, Nrf2 plays a dual role. Activation of Nrf2 protects cells from carcinogens. However, once a tumour has developed, Nrf2 can be hijacked by cancer cells to induce chemoresistance. This study examined the role of Nrf2 in malignant melanoma cells. Nrf2 was found to be overexpressed in 11 human melanoma cell lines in comparison with melanocytes. Chemoresistance to dacarbazine, doxorubicin and cisplatin correlated with Nrf2 expression, and Nrf2 siRNA increased the susceptibility of M202 and SK-MEL-5 cells to cisplatin, suggesting that Nrf2 plays a role in chemoresistance in melanoma. In conclusion, this study has identified novel activators of Nrf2, including a dietary compound and a cell penetrating peptide which inhibits inflammation in vitro. In addition, Nrf2 inhibition sensitises melanoma cells to chemotherapy. These results suggest that targeting Nrf2 is a viable strategy in both inflammation and cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.656116  DOI: Not available
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