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UBC Theses and Dissertations

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UBC Theses and Dissertations

Regulation of primary, immortalized, and metatstatic human pancreatic ductal cells by insulin Chan, Michelle Tsz Ting

Abstract

Epidemiological studies have reported positive correlation between type 2 diabetes and risk of pancreatic cancer. Hyperinsulinemia occurring during early diabetes has been postulated to be a possible pathophysiological mechanism in promoting pancreatic cancer, but the mechanisms by which elevated insulin levels contribute to pancreatic carcinogenesis are still unknown. Here, the effects of insulin and its associated mechanism on cellular viability were examined in three cell models that are meant to represent three stages in pancreatic cancer progression. Furthermore, using small molecule inhibitors, the role of RAF/ERK pathway and PI3K/AKT pathway on cellular viability were also compared across three cell models. Different stages of pancreatic cancer progression were modeled in vitro with primary human pancreatic ductal cells, an immortalized pre-malignant human pancreatic ductal cell line (HPDE), and an advanced metastatic human pancreatic adenocarcinoma cell line (PANC1). All cell types were serum starved and treated with insulin, IGF1, or small molecule inhibitors targeting RAF1, MEK, AKT, or PI3K, then subjected to cell viability assays, cell death assays, and Western blot analysis for ERK and AKT activation. We observed that cell viability was promoted by exogenous insulin in PANC1 cells, and not in primary cells. In PANC1 cells, the insulin-mediated enhancement of cell viability was associated with sustained AKT activation. Furthermore, insulin-mediated reduction in cell death was not observed. When comparing the roles of RAF/ERK and PI3K/AKT pathways on cell viability, we observed an increase in cell death in primary cells when AKT was inhibited. In contrast, cell death was induced in HPDE and PANC1 cells when the RAF1 or MEK were inhibited. If extrapolated, the data suggest that hyperinsulinemia may not play a role in initiating pancreatic cancer, but high levels of insulin may accelerate the cancer progression.

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