Date of Award
Cell viability, Cholesterol, Colorectal Cancer, HMGCR, LDLR, MAPK
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Colorectal cancers (CRC) express high level of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) protein suggesting an increased requirement for endogenous cholesterol biosynthetic pathway by growing cancer cells. Intake of statins, pharmacological inhibitors of HMGCR has been reported to exert varying responses in reducing the risk of CRC in humans, suggesting the existence of tumours with statin-sensitive and statin-resistant phenotypes. Normally intracellular cholesterol homeostasis involves several proteins including HMGCR and the membrane bound low density lipoprotein receptor (LDLR) which allows uptake of plasma cholesterol and increase intracellular cholesterol level. Therefore, HMGCR activity within a cell is highly dependent on the level of LDLR. Whether LDLR is playing a role in CRC growth and cholesterol homeostasis remains poorly understood. In the first study, it was observed that experimentally induced colonic tumours, express lower LDLR and higher HMGCR, SREBP2 (Sterol Regulatory Element Binding Protein) and PCSK9 (Proprotein convertase subtilisin/kexin type 9) compared to colonic mucosa. This observation led to the hypothesis that a low LDLR phenotype favours tumour growth. To test this hypothesis, three human colorectal cancer cell lines (HCT 116, HT 29 and DLD 1) were selected. Through Western blot analysis and q-RT-PCR, it was established that all three cancer cell lines express lower levels of LDLR and higher levels of HMGCR, SREBP2 and PCSK9 compared to normal colonic epithelial cells, similar to solid tumours. DLD1 cells expressing the lowest LDLR protein exhibited the highest cell viability and proliferation amongst the three cancer cell lines. HCT 116 and HT 29 showed higher sensitivity to the growth inhibitory effect of cholesterol lowering drugs such as lovastatin and RO 48-8071 and were able to upregulate LDLR unlike DLD 1 cells. Ectopic overexpression of LDLR in the three CRC cell lines was associated with reduced cell viability, cell motility and migration and enhanced growth inhibition by lovastatin. Furthermore, ectopic over expression of LDLR induced tumour suppressive p38 and PTEN signaling and reduced activation of pro-survival signaling proteins such as ERK1/2and AKT. The present dissertation alludes to a novel role of LDLR in CRC development. More importantly the findings support a tumour suppressive role of elevated LDLR in CRC and support the contention that the drugs being used to inhibit HMGCR and/or increase LDLR, for the prevention of coronary artery diseases could also be effective in the prevention of CRC.
Basu, Vaishali, "Role of Low Density Lipoprotein Receptor as a Potential Suppressor of Growth and Survival of Colorectal Cancer Cells" (2017). Electronic Theses and Dissertations. 5929.