Author ORCID Identifier
https://orcid.org/0009-0002-5389-9702
Defense Date
2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human and Molecular Genetics
First Advisor
Senthil Radhakrishnan
Abstract
Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates the synthesis of new proteasomes, thus enabling cells to mitigate proteotoxic stress. Here, we report that under similar circumstances, multiple components of the autophagy-lysosomal pathway (ALP) were transcriptionally upregulated in an Nrf1-dependent fashion, thus providing the cells with an additional route to cope with proteasome insufficiency. In response to proteasome inhibitors, Nrf1-deficient cells exhibited profound defects in inducing autophagy and clearing aggresomes. This phenomenon was also recapitulated in NGLY1 knockout cells, where Nrf1 is known to be non-functional. Conversely, overexpression of Nrf1 induced ALP genes and endowed the cells with an increased capacity to clear aggresomes. Overall, our results significantly expand the role of Nrf1 in shaping the cellular response to proteotoxic stress.
Proteasome inhibitors, ixazomib, carfilzomib, and bortezomib, are FDA-approved and currently used in clinics to treat multiple myeloma and mantle cell lymphoma. However, over time, patients often develop resistance to proteasome inhibitors, rendering them less effective as a treatment. The transcription factor Nrf1 induces proteasome and autophagy-lysosomal pathway (ALP) genes in response to proteasome inhibition, thus making proteasome inhibitors less effective. To improve the efficacy of proteasome inhibitors, it is necessary to identify drugs that can attenuate the Nrf1-mediated bounce-back response. Here, we found that anthracyclines, such as doxorubicin, synergized with proteasome inhibitors. Anthracyclines were able to attenuate Nrf1 transcriptional activity and increase cancer cell death. Moreover, we found that anthracyclines inhibited Nrf1's ability to bind to antioxidant response elements (AREs) of target genes for the proteasome and ALP. Interestingly, we also saw that aclarubicin, a non-DNA damage-inducing anthracycline, was also able to attenuate the Nrf1-mediated bounce-back response. Our work provides a mechanistic explanation of the synergy between anthracyclines and proteasome inhibitors in cancer cell lines, and these findings could lead to future preclinical and clinical studies for this combinational treatment.
Rights
© Madison A. Ward
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-31-2025