Jumbo, Ugonma Kendra (2026) Modulation Of Metabolic and Autophagic Survival Pathways to Enhance Chemosensitivity in Pancreatic Cancer Cell Lines. Masters thesis, York St John University.

Text (Masters by Research thesis) Modulation Of Metabolic and Autophagic Survival Pathways to Enhance Chemosensitivity in Pancreatic Cancer Cell Lines.pdf - Published Version Restricted to Repository staff only until 7 September 2027. Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (2MB) Request a copy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive forms of cancer with poor prognosis due to resistance to standard treatments. Treatment of pancreatic cancer include surgical resection and systemic therapy. Emerging evidence suggests that metabolic stress may sensitise cancer cells to gemcitabine-mediated cytotoxicity, thereby enhancing therapeutic efficacy. This study investigated the effect of combination treatment of gemcitabine with the metabolic stressor metformin. In addition, the autophagy inhibitor hydroxychloroquine (HCQ) was also assessed for influencing gemcitabine-sensitivity and autophagy flux in Panc-1 and MIA PaCa-2 pancreatic cancer cell lines.

MIA PaCa-2 cells were more sensitive to gemcitabine (<50% viability at 100 nM) than Panc-1 cells, which were largely resistant to gemcitabine (81% viability at 100 nM). While metformin concentrations used (0.1 μM – 100 μM) did not significantly impact cell viability (p > 0.05), Western blot analysis showed that it increased autophagic flux in Panc-1 cells through an accumulation of p62 protein (p < 0.0001), suggesting a potential protective survival mechanism.

HCQ was combined with gemcitabine to inhibit lysosomal degradation and counter autophagy mediated survival. This co-treatment led to substantial autophagy blockade, particularly in MIA PaCa-2 cells, with a 49-fold accumulation of p62 and a 27-fold increase in LC3-II (p < 0.0001). These findings indicate that metabolic stress can activate autophagy-mediated survival pathways, but pharmacological blockade with HCQ converts this pathway into a cytotoxic mechanism. Overall, this study provides further understanding of potential therapeutic strategies targeting autophagy in combination with standard chemotherapy.

Item Type:	Thesis (Masters)
Status:	Published
Subjects:	Q Science > Q Science (General)
School/Department:	School of Science, Technology and Health
URI:	https://ray.yorksj.ac.uk/id/eprint/15761

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