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Title: Targeting FOXO3a and sirtuins in breast cancer
Author: Peck, Barrie
ISNI:       0000 0004 2700 268X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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SIRT proteins play an important role in the survival and drug resistance of tumour cells, especially during chemotherapy. In this study, we investigated the potency, specificity and cellular targets of three recently identified SIRT inhibitors, Sirtinol, Salermide and EX527. Our results identify the specificity and cellular targets of these novel inhibitors, and suggest that SIRT inhibitors require combined targeting of both SIRT1 and SIRT2 to induce p53 acetylation and cell death in breast cancer cells. Assessing the role of sirtuins in chemoresistance, cisplatin resistant cell lines were developed and characterized. Cisplatin resistant cells (CisR) were found to have higher levels of SIRT1, repressing the activation of FOXO3a. MCF-7 cells overexpressing SIRT1 were also shown to be protected against cisplatin treatment, highlighting its role in resistance. Sirtuins have many cellular targets, including alpha-tubulin, PARP, ku70 and FOXO3a. Because of the similarities between the regulation of p53 and FOXO3a, we decided to elucidate the effect of sirtinol treatment on FOXO3a. Sirtinol treatment was shown to stabilize FOXO3a, similar to its effect on p53, but at lower concentrations. We have shown previously that FOXO3a is an important downstream mediator of the cytotoxicity of receptor tyrosine kinase targeted therapies. To examine the conjecture whether sirtuin inhibitors could increase the proapoptotic potency of lapatinib through stabilization of FOXO3a, lapatinib was treated alone and in combination with sirtinol and EX527. Sirtinol was found to synergise with lapatinib treatment (in cells containing mutant p53) and this was dependent on the presence of FOXO proteins, highlighting the use of sirtuin inhibitors in increasing the efficacy of therapies that indirectly target FOXO3a.
Supervisor: Lam, Eric Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral