Date of Award

2026-05-01

Degree Name

Doctor of Philosophy

Department

Biosciences

Advisor(s)

German Rosas-Acosta

Abstract

Post-translational modifications (PTMs) are critical regulators of protein function, stability, and localization, with SUMOylation emerging as a key modulator of cellular stress response and survival in cancer. Non-small cell lung cancer (NSCLC) is characterized by heightened dependence on SUMOylation to sustain pro-survival signaling, DNA repair, and resistance to chemotherapy. This dissertation investigates a novel chemosensitization strategy based on the splice-switching of SUMO transcripts in NSCLC cells using exon-skipping morpholinos (ESMs), which redirect splicing toward non-conjugatable SUMO alpha isoforms, thereby reducing global SUMOylation. We hypothesized that decreasing global SUMOylation through forced alternative splicing of SUMO transcripts would impair the stress-protective functions of the SUMO pathway and enhance the cytotoxic efficacy of cisplatin and etoposide, the standard-of-care chemotherapeutic agents for NSCLC. To test this hypothesis, we employed an in vitro experimental framework utilizing cytotoxicity assays, colony formation, cell cycle progression analysis, and cell migration assays in NSCLC cell lines treated with ESMs in combination with chemotherapy. The findings of this dissertation provide preclinical proof-of-concept for targeting the SUMO paralogs as a chemosensitization strategy and establish a mechanistic basis for disrupting SUMOylation in NSCLC. This work has broader implications for other SUMO-dependent malignancies and advances the foundation for targeting alternative splicing as an approach into clinical therapeutic development.

Language

en

Provenance

Received from ProQuest

File Size

119 p.

File Format

application/pdf

Rights Holder

Andrea Teresa Garcia-Morin

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