Targeting Cancer Cell Persistence: The Role of Mitochondrial Dynamics in Modulating the Integrated Stress Response
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Authors
Opoka, Monica Daria
Date
2024-11-01
Type
thesis
Language
eng
Keyword
integrated stress response , ATF4 , mitochondrial dynamics , DRP1 , OPA1 , drug-tolerant persister , drug resistance , cancer , triple-negative breast cancer
Alternative Title
Abstract
Cancer cells that survive cytotoxic therapies, termed drug-tolerant persister (DTP) cells, can contribute to cancer recurrence. New studies suggest that the aggressive phenotype of DTP cells is driven in part by incomplete apoptotic commitment. Specifically, sublethal cytochrome c release from mitochondria could activate the integrated stress response (ISR) and downstream adaptive transcriptional changes mediated by activating transcription factor 4 (ATF4). However, the ISR counterbalances cell survival and apoptosis depending on the context, supporting the need for a more detailed understanding to effectively target this pathway in cancer. Interestingly, cytochrome c release for apoptosis initiation is also dependent upon the remodelling of mitochondrial membranes. The dynamic remodelling of mitochondria involves fission and fusion events, each controlled by GTPase proteins. Thus, we hypothesized that mitochondrial dynamics could regulate ISR activation in DTP cells via modulation of cytochrome c. Our results revealed that knockdown (KD) of the mitochondrial fission mediator, Drp1, in human triple-negative breast cancer (TNBC) MDA-MB-231 cells strongly induced the ISR through increased expression of ATF4 and its downstream target genes involved in amino acid metabolism, redox balance, and autophagy. In contrast, KD of the mitochondrial fusion mediator, Opa1, induced a weaker ISR. Unexpectedly, despite the induction of a stronger ISR by Drp1 KD, TNBC anchorage-independent cell proliferation potential was suppressed to a greater degree by Opa1 KD than Drp1 KD. This suggests complex dependency on a multitude of metabolic, inflammatory, and cell-cycle related factors. Furthermore, we found that Drp1 deficient cells displayed notably higher apoptosis and DNA damage levels induced by BH3-mimetic treatment, which correlated with increased ATF4 activation. Therefore, inhibition of mitochondrial fission may enhance ISR signaling to amplify chemotherapy-induced apoptosis in a feedback loop. We found that the ISR appears to play a role in promoting drug tolerance to diverse anti-cancer therapies, implicating the ISR as a potential target for these treatments. Overall, these findings suggest that Drp1-mediated mitochondrial fission is a key regulator of ISR activation. Targeting Drp1 could represent a promising strategy to increase DTP cell chemosensitivity and reduce cancer persistence.
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Attribution-NoDerivatives 4.0 International
ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NoDerivatives 4.0 International