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Title: FOXM1 mediates the response to 5-fluorouracil via thymidylate synthase in colorectal cancer
Author: Varghese, Vidhya
ISNI:       0000 0004 6422 7052
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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5-Fluorouracil (5-FU) is the most commonly used drug in the treatment of colorectal cancer (CRC). Tumour resistance to chemotherapy is a major challenge in cancer therapeutics, which ultimately leads to treatment failure and disease progression. Studies which investigate the mechanisms underpinning drug resistance may provide opportunities for the development of novel agents, and allow the early prediction of tumour sensitivity to specific agents. Resistance to 5-FU has been linked to elevated expression of the main 5-FU target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. FOXM1 is a critical regulator of the G1/S and G2/M cell cycle transitions. Emerging evidence suggests that elevated tumour levels of FOXM1 are associated with a variety of aggressive human cancers and chemotherapy resistance, but little is known about their role in colorectal cancer and specifically in respect to 5-FU. In this study, I investigated the role of FOXM1 in CRC 5-FU drug resistance. This study reveals a significant role of FOXM1 in 5-FU drug resistance. Over- expression and knock-down of FOXM1 in colon cancer cells suggests that FOXM1 regulates TYMS. ChIP data also confirms that FOXM1 mediates 5-FU drug resistance mainly through the regulation of TYMS, and the additional 5-FU targets thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining were observed. Elevated FOXM1 and TYMS expression were also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an antagonist of FOXM1, thiostrepton in combination with 5-FU. The combination treatment decreases colony formation and migration, and induces cell cycle arrest, DNA damage, and caspase 3/7 dependent apoptosis in CRC cell lines. I also studied the effect of E2F transcription activators (E2F1, E2F2 and E2F3) on 5-FU resistance as E2F1 is known to regulate FOXM1 and TYMS independently. I observed that in addition to E2F1, E2F2 and E2F3 can regulate TYMS and FOXM1. Furthermore I identified the binding sites of FOXM1 on E2F1 and E2F2 transcription activators, and knock-down of E2F1 increases resistance towards 5-FU in p53 mutant and HCT116 5-FU Res cells, indicating the importance of E2F1 in apoptosis. In summary, this research demonstrated that FOXM1 plays a pivotal role in TYMS mediated 5-FU resistance. Direct targeting of FOXM1 in combination with 5-FU would be a better strategy than 5-FU alone in circumventing 5-FU resistance and provide a platform for further evaluation of FOXM1 targeted therapies as a mechanism to overcome 5-FU resistance. This finding should have important clinical implications for exploiting FOXM1 to prevent 5-FU drug resistance and subsequent metastasis in colorectal cancer patients.
Supervisor: Kenny, Laura ; Lam, Eric Sponsor: National Institute for Health Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral