Studies of drug resistance mostly characterize genetic mutations, and we know much less about the phenotypic mechanisms of drug resistance, especially at a quantitative level. p53 is an important mediator that regulates the cellular response to chemotherapy, but even cancer cells with wild-type p53 exhibited variable drug sensitivity for unclear reasons. In this PhD thesis, I investigated the mechanistic basis underlying differential p53 pathway activation in response to two types of chemotherapeutics, i.e., etoposide (a DNA-damaging drug) and 5-fluorouracil (5-FU, an antimetabolites), which led to distinct cell fate outcome in drug sensitive vs. resistant cancer cells. Specifically, I uncovered a new resistance mechanism to etoposide through bimodal modulation of p53 activation dynamics and characterized a four-component regulatory module, involving ATM, p53, Mdm2 and Wip1, which generates bimodal p53 dynamics through coupled feed-forward and feedback loops. Moreover, I found that the inhibitory strength between ATM and Mdm2 determined the differential modular output between drug sensitive and resistant cancer cell lines, and that combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response, pointing to p53 pulsing as a potentially druggable mechanism that mediates resistance to DNA damaging chemotherapy. As for response to 5-FU, preliminary results illustrated that 5-FU activated p53 and differential cell fate outcome via ribosomal stress, rather than DNA damage. Different from dose response to etoposide, 5-FU-induced p53 activity was not only regulated by p53 induction level but also p53 phosphorylation by kinases, such as DNA-PK. Overall, this thesis presented original results that elucidated phenotypic mechanism of chemoresistance and provide new angles towards developing more effective combinatorial anticancer therapy.
| Identifer | oai:union.ndltd.org:hkbu.edu.hk/oai:repository.hkbu.edu.hk:etd_oa-1649 |
| Date | 15 August 2019 |
| Creators | Yang, Ruizhen |
| Publisher | HKBU Institutional Repository |
| Source Sets | Hong Kong Baptist University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Open Access Theses and Dissertations |
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