Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.818817
Title: Investigation of non-canonical effects of BH3-mimetic compounds
Author: Roca-Portoles, Alba
ISNI:       0000 0004 9356 1367
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2020
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Abstract:
Apoptotic cell death is almost universally considered a beneficial process that acts to both prevent and treat cancer. Exploiting this, drugs called BH3-mimetics that inhibit anti-apoptotic Bcl-2 proteins and thereby induce apoptosis, have been designed to sensitise cancer cells to apoptosis. There are a wide variety of BH3-mimetics targeting Bcl-2 proteins, and they display potent effects in some cancer types. However, the role of apoptosis in cancer may be more complex than initially thought, as oncogenic properties of apoptosis have also been described. Here, I have investigated the effects of BH3-mimetics (apoptotic-inducers) in different cancer types. Amongst other non-canonical effects such as inflammation, I have also found metabolic effects induced by BH3-mimetics. Most of these metabolic effects were cell-type dependent, however, the specific BCL-2 inhibitor ABT-199 (also called venetoclax) demonstrated the most consistent results. ABT-199 altered cellular metabolism by inhibiting mitochondrial respiration and inducing reductive carboxylation. Surprisingly, these metabolic alterations were independent of its well-known target BCL-2, although they were dependent on the transcription factor ATF4. ATF4 is involved in the integrated stress response (ISR) and it regulates the transcription of several metabolic enzymes. Importantly, both metabolic reprogramming and ATF4 upregulation have been described as mechanisms of chemoresistance. Thus, by demonstrating that ABT-199 rewires metabolism through ATF4 activation, it may indicate a mechanism to promote tumour resistance upon ABT-199 treatment, which may have further implications for therapy. Overall, I have found that induction of mitochondrial stress rather than apoptosis per-se induced by BH3-mimetics may be oncogenic. Thus, I have uncovered non-canonical roles of these drugs that are implicated in inflammation and metabolism of cancer cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.818817  DOI: Not available
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