Effects of insulin on human pancreatic cancer progression modeled in vitro

BMC Cancer

James D Johnson¹  Garth L Warnock¹  James M Piret²  Corinne A Hoesli³  Emilyn U Alejandro⁴  Tobias Albrecht⁴  Yu Hsuan Carol Yang⁴  Søs Skovsø⁴  Gareth E Lim⁴  Michelle T Chan⁴ 

[1]Department of Surgery, University of British Columbia, Vancouver, BC, Canada

[2]Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, BC, Canada

[3]Present address: Département de génie chimique | Department of Chemical Engineering, Université McGill University, 3610 University Street, Wong Building, Room 4230, Montréal H3A 0C5, Canada

[4]Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada

关键词: ERK;    AKT;    Pancreatic ductal adenocarcinoma;    PDAC;    Diabetes;    HPDE;    PANC1;    Pancreatic cancer;    Hyperinsulinemia;   

Others  :  1120231
DOI  :  10.1186/1471-2407-14-814

 received in 2014-03-07, accepted in 2014-10-27,  发布年份 2014

【 摘 要 】

Background

Pancreatic 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.

Methods

Here, 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.

Results

While 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.

Conclusions

Our 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.

【 授权许可】

   
2014 Chan et al.; licensee BioMed Central Ltd.

【 图 表 】

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