Investigating the Effect of Cholesterol Depletion on IL-6 Cytokine Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer globally. Poor patient prognosis is attributed to late diagnosis and high metastatic potential of the disease. The process of metastasis usually favours the conversion between epithelial and mesenchymal cellular states, termed epithelial-to-mesenchymal transition (EMT). EMT has been reported to contribute to drug resistance, following treatments with chemotherapy, which allows for cancer recurrence and metastasis. Additionally, increasing evidence indicates the role of the cholesterol biosynthesis pathway in EMT progression. The lipid composition of epithelial cells compared to mesenchymal cells is distinct and cells that undergo EMT show an elevation in cholesterol levels to facilitate increased proliferation and oncogenic signalling. This study aimed to investigate the effect of cholesterol depletion in EMT induced CRC and explored how cholesterol depletion influences the susceptibility of EMT induced cells to the chemotherapy cocktail referred to as FOLFOX (5-fluorouracil and oxaliplatin). Results showed that following EMT induction by proinflammatory cytokine interleukin-6 (IL-6), in HT-29 cells, cellular cholesterol content increased by ~30%. Cholesterol depletion with compounds methyl-β-cyclodextrin (MβCD) and KS-01, in post-EMT cells, showed to reverse EMT phenotypic changes as noted by increased epithelial marker E-cadherin (by 46.9% and 55.3%, respectively), decreased mesenchymal marker vimentin (by 41.0% and 52.8%, respectively) and reduced invasive potential (by 43.0% and 47.8%, respectively). Interestingly, EMT induced cells displayed increased sensitivity to the FOLFOX chemotherapy, following cholesterol depletion, as observed by enhanced susceptibility to apoptosis (by 46.7% and 60.3%, respectively) and attenuation of multidrug resistance (by 80.6% and 71.8%, respectively). Ultimately, this study highlights cholesterol depletion to be a promising strategy for potential treatment of metastatic CRC.