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Title: Dihydroorotate dehydrogenase regulates ER membrane reorganisation and cell death in cancer
Author: Yedida, Govinda
ISNI:       0000 0004 9358 4307
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2020
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The endoplasmic reticulum (ER) exists as an elaborated network of flat sheets and cylindrical tubules. ER network interacts with several other organelles, including mitochondria to play a vital role in membrane dynamics and other functions. However, the impact of ER-mitochondrial interactions on apoptosis is poorly understood. Cancer cells acquire resistance to anti-cancer agents through different mechanisms, including failure to undergo apoptosis. Therefore, better understanding of ER-mitochondrial communications and their impact on apoptosis could unravel mechanisms of drug resistance. We have previously observed a reversible reorganisation of ER membranes in cells exposed to several pharmaceutical agents. Hence, we conducted this study using ER membrane reorganisation as a tool to explore ER-mitochondrial communication and how it impacts mitochondrial-mediated apoptosis. This thesis is divided into three results chapters. In the first results chapter, using apogossypol as a prototype tool compound, it is shown that ER membrane reorganisation occurs at the level of ER tubules but does not involve ER sheets. Moreover, further characterisation of the subcellular localisation of reorganised membranes reveal that other organelles, such as mitochondria, lysosomes, Golgi complex were not involved in ER membrane reorganisation. Next, the effect of ER membrane reorganisation with respect to mitochondrial membrane dynamics and apoptosis was studied. The results indicate that ER membrane reorganisation prevents DRP-1-mediated mitochondrial fission as well as BH3 mimetic-mediated BAX translocation, cytochrome c release and apoptosis. In the next results chapter, the objective was to examine the impact of ER membrane reorganisation modulators on apoptosis. Inhibitors of dihydroorotate dehydrogenase (DHODH), such as teriflunomide and leflunomide, not only prevent ER membrane reorganisation, but also antagonise the protective effects of the reorganised ER membranes against BH3 mimetic-mediated apoptosis. Since DHODH inhibitors antagonised ER membrane reorganisation and enhanced BH3 mimetic-mediated apoptosis, in the next chapter, the therapeutic benefits of DHODH inhibitors was explored in head and neck squamous cell carcinoma (HNSCC). The results indicate that DHODH is highly expressed in HNSCC cell lines, and genetic as well as pharmacological inhibition of DHODH reduce clonogenic survival potential in several HNSCC cells. Although targeting DHODH could be a promising strategy in HNSCC, inhibitors of DHODH do not synergise with other potential chemotherapeutic agents namely, cisplatin, A-1331852, S63845, and CB-839. Further studies are required to assess whether DHODH inhibitors will be effective as single agents, or in combination with other novel chemotherapeutic agents.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral