The role of FOXO3a in the cellular stress response and metabolism of breast cancer cells

• Main Author: Wilson, Miranda Sophie Claire
• Other Authors: Lam, Eric
• Published: Imperial College London 2012
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560735

The development of acquired resistance to chemotherapeutic drugs is often a limiting factor in the treatment of cancer. In this study, I investigated alterations in MAP kinase signalling and metabolism in a doxorubicin/epirubicin-resistant breast cancer cell line. Doxorubicin, also known as adriamycin, is one of the most important drugs in the treatment of breast cancer. The MAP kinases ERK, JNK, and p38 have all been linked to drug response and tumorigenesis, as well as apoptosis, in different cell types. I found that ERK activity was downregulated in the resistant cell line, while transcripts of the ERK phosphatases DUSP5 and DUSP6 were enriched. The resistant cells also contain less FOXO3a, a broadly pro-apoptotic transcription factor that regulates many aspects of cellular activity. I also used NMR-based metabonomics to generate a metabolic profile of the parental and doxorubicin-resistant cell lines. Many metabolic changes are seen during tumorigenesis, with further changes seen after the development of drug resistance. An increase in glycolysis is the best known, but alterations in choline metabolism and glutamine usage are also commonly seen in cancer. My results confirmed an increase in glycolysis in the resistant cells, as well as altered glutamine metabolism, and also provided novel findings for future work. The reduction in intracellular glutamine in the resistant cells was correlated with a loss of expression of the metabolic enzyme glutamine synthetase. My results show that the doxorubicin-sensitive parental cell line expresses glutamine synthetase, which was required for maximal proliferation rate. Conversely, the lack of glutamine synthetase in the doxorubicin-resistant cells caused them to be dependent on the provision of extracellular glutamine for growth. This may have implications for the treatment of drug resistant breast cancers.