Defense Date

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Human and Molecular Genetics

First Advisor

Dr. Senthil Radhakrishnan

Abstract

Cancer cells exhibit a heightened dependence on proteasome activity, which can support pro-tumor cellular processes and compensate for inherent genetic instability, thus proteasome inhibition is used chemotherapeutically to inhibit proteasome-dependent cancer processes and induce fatal proteotoxic stress. Proteasome inhibitors have only achieved clinically significant outcomes in patients with hematologic cancers, though with frequently observed intrinsic and acquired resistance. The highly-conserved proteasome bounce-back response describes a compensatory cellular mechanism to overcome diminished proteasome activity, in which the diminished activity triggers the transcriptional activation of proteasome subunit (PSM) genes by NRF1, resulting in the de novo assembly of active proteasomes to rescue the proteasome activity. We sought to evaluate the efficacy of a combinational therapy to potentiate proteasome inhibition by simultaneously inhibiting the NRF1-mediated proteasome bounce-back response, a potential proteasome inhibitor resistance mechanism. Building on our previous work that demonstrated potentiation of proteasome inhibition by NRF1 knockdown in a TNBC cell line in vitro, we found that NRF1 depletion in a TNBC xenograft mouse model sensitized the tumors to proteasome inhibition in vivo. Depletion and mutation of the NRF1-activating aspartyl protease DDI2 also inhibited the proteasome bounce-back response, leading to potentiation of carfilzomib’s cytotoxic effects in TNBC cells in vitro. Our results provide a strong rationale for simultaneous inhibition of the proteasome and NRF1-mediated proteasome bounce-back response to increase the efficacy of proteasome inhibitors. Potentiated proteasome inhibition could potentially expand the repertoire of cancer types in which proteasome inhibitors are therapeutically useful to include non-hematologic malignancies, such as breast cancer.

Rights

© Amy Virginia Northrop

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-4-2020

Available for download on Saturday, June 17, 2220

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