Role of cholesterol in colon cancer and its impact on AOM/DSS induced mouse intestinal tumourigenesis


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Shyamananda Singh Mayengbam1,Manoj Kumar Bhat1
1National Centre for Cell Science, Savitribai Phule Pune University, Pune, India

Abstract

Background

Clinical studies show a significant correlation in alteration of blood cholesterol level with colon cancer. Numerous studies have reported that blood cholesterol level often decreases in colon cancer patient, which is also negatively correlated with stage of tumour. We investigate the role of cholesterol in lipid and glucose metabolism of colon cancer along with various other signalling molecules.

Method

For understanding the role of cholesterol in colon cancer, long term colony formation, enzyme activity assay, glucose & lactate estimation were performed in HCT116 p53+/+ and p53-/- cells in the presence or absence of low density lipoprotein cholesterol (LDLc) and high density lipoprotein cholesterol (HDLc). Immunoblot and confocal microscopy for studying molecular events associated with cholesterol and colon cancer. C57BL/6J mice were used for in vivo isograft and chemically induced (AOM/DSS) colon cancer model.

Results

In vivo studies shows that mice fed on high cholesterol diet and high fat diet increases the incidence of AOM/DSS induced polyp formation, indicative of colon cancer when compared to mice fed with normal diet. Moreover, our in vitro result shows that, supplementation of LDLc and HDLc also increases colon cancer cell proliferation through ERK activation. We found that treatment of LDLc and HDLc increases glycolytic enzyme activities thereby enhancing glucose utilization and lactate production which in turns triggers the overexpression of monocarboxylate transporter 4 (MCT-4) for lactate efflux. Apart from increased enzyme activity, it also facilitates intracellular cholesterol accumulation and lipid droplet formation along with the up-regulation of LDL receptor (LDLR).

Conclusion

Both in vitro and in vivo results show a positive correlation of cholesterol with colon cancer cell proliferation and incidence. The role of cholesterol in lipid and glucose metabolism in colon cancer cells needs further investigation. Deciphering the underlying molecular mechanism of cholesterol associated events in colon cancer will help in better management of colon cancer.