How does insulin exposure affect tumour cell metabolism at different stages of colorectal carcinogenesis?


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Amy Holt1,Aleksandra Ryk1,Danny Legge1,Caroline Bull1,Tracey Collard1,Ann Williams1,Emma Vincent1
1University of Bristol

Abstract

Background

Type 2 diabetes and nutritional factors, notably obesity, are associated with hyperinsulinaemia, leading to the exposure of the body’s cells and tissues to excess levels of insulin. Hyperinsulinaemia has long been cited as a plausible mechanistic explanation for the increased risk of certain cancers in people with type 2 diabetes. While the mitogenic properties of insulin have been extensively studied, the impact of insulin on tumour cell metabolism has not been explored. Metabolic reprogramming is a hallmark of cancer and a requirement for tumour cells to support chronic proliferation.

Method

We use a cell line series representing an in vitro model of tumour progression (adenoma to carcinoma sequence of the same lineage) alongside commercially available colorectal carcinoma cell lines. This allows us to assess the impact of insulin across the stages of carcinogenesis. We assess cellular proliferation (using a crystal violet-based assay), cellular signalling (using western blotting) and cellular metabolism (using extracellular flux analysis and mass spectrometry). 

Results

Proliferation of cell lines representing the early stages of colorectal tumour development is increased upon incubation with insulin, whereas proliferation of carcinoma (late stages of tumour development) cell lines is not. Insulin exposure reprograms cellular metabolism to promote glycolysis and reduce carbon entry into the TCA cycle. Increased pyruvate dehydrogenase kinase 1 (PDK1) expression in response to insulin exposure may be responsible for this. 

Conclusion

Insulin exposure impacts proliferation of early (but not late stage) adenoma cell lines and induces metabolic reprogramming. Increased expression of PDK1, occurring in response to insulin treatment, may promote a shift to glycolytic over oxidative metabolism known as Warburg effect.