Abstract
BackgroundPancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. Hyperinsulinemia has been reported to be a risk factor of pancreatic cancer, and the rapid rise of hyperinsulinemia associated with obesity and type 2 diabetes foreshadows a rise in cancer incidence. However, the actions of insulin at the various stages of pancreatic cancer progression remain poorly defined.MethodsHere, we examined the effects of a range of insulin doses on signalling, proliferation and survival in three human cell models meant to represent three stages in pancreatic cancer progression: primary pancreatic duct cells, the HPDE immortalized pancreatic ductal cell line, and the PANC1 metastatic pancreatic cancer cell line. Cells were treated with a range of insulin doses, and their proliferation/viability were tracked via live cell imaging and XTT assays. Signal transduction was assessed through the AKT and ERK signalling pathways via immunoblotting. Inhibitors of AKT and ERK signalling were used to determine the relative contribution of these pathways to the survival of each cell model.ResultsWhile all three cell types responded to insulin, as indicated by phosphorylation of AKT and ERK, we found that there were stark differences in insulin-dependent proliferation, cell viability and cell survival among the cell types. High concentrations of insulin increased PANC1 and HPDE cell number, but did not alter primary duct cell proliferation in vitro. Cell survival was enhanced by insulin in both primary duct cells and HPDE cells. Moreover, we found that primary cells were more dependent on AKT signalling, while HPDE cells and PANC1 cells were more dependent on RAF/ERK signalling.ConclusionsOur data suggest that excessive insulin signalling may contribute to proliferation and survival in human immortalized pancreatic ductal cells and metastatic pancreatic cancer cells, but not in normal adult human pancreatic ductal cells. These data suggest that signalling pathways involved in cell survival may be rewired during pancreatic cancer progression.
Highlights
Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood
The total amount of ERK tended to be slightly higher in the HPDE cell line, whereas the baseline phosphorylation status of ERK on T402/Y204 was consistently higher in PANC1 cells (Figure 1)
The aim of the present study was to determine whether the response to insulin was different between primary human pancreatic ductal cells, an immortalized pancreatic ductal cell line (HPDE), and an advanced pancreatic cancer cell line (PANC1)
Summary
Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. The actions of insulin at the various stages of pancreatic cancer progression remain poorly defined. The average 5-year survival rate for pancreatic cancer remains below 5%, which underscores the need to identify key risk factors is imperative to investigate the effects of insulin on different stages of pancreatic cancer progression. The molecular mechanisms by which hyperinsulinemia may affect pancreatic cancer progression remain incompletely understood, but several studies have demonstrated the importance of the RAS-MEK-ERK pathway and the PI3K-AKT pathway. The KRasG12D mutation leads to constitutive activation of RAF-MEK-ERK and PI3K-AKT cascades to drive uncontrolled growth, proliferation and survival of cancer cells [10]. Active AKT can transform normal mouse pancreatic duct cells into malignant pancreatic cancer cells in vivo [15], but the inability of PI3K-AKT inhibition to affect several Ras-driven cancers suggests that KRas acts on multiple pathways in oncogenesis [10,16,17]
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