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Pancreatic cancer remains one of the most lethal cancers due to late diagnosis and high chemoresistance. Despite recent progression in the development of chemotherapies, immunotherapies, and potential nanoparticles-based approaches, the success rate of therapeutic response is limited which is further compounded by cancer drug resistance. Understanding of emerging biological and molecular pathways causative of pancreatic cancer's aggressive and chemoresistance is vital to improve the effectiveness of existing therapeutics and to develop new therapies. One such under-investigated and relatively less explored area of research is documenting the effect that lipids, specifically cholesterol, and its metabolism, impose on pancreatic cancer. Dysregulated cholesterol metabolism has a profound role in supporting cellular proliferation, survival, and promoting chemoresistance and this has been well established in various other cancers. Thus, we aimed to provide an in-depth review focusing on the significance of cholesterol metabolism in pancreatic cancer and relevant genes at play, molecular processes contributing to cellular cholesterol homeostasis, and current research efforts to develop new cholesterol-targeting therapeutics. We highlight the caveats, weigh in different experimental therapeutic strategies, and provide possible suggestions for future research highlighting cholesterol's importance as a therapeutic target against pancreatic cancer resistance and cancer progression. Schematic illustrating the broad cholesterol-related mechanisms, such as increased cholesterol synthesis, uptake and storage, with reduced cholesterol efflux leading to a high intratumoural cholesterol content aiding in pancreatic cancer progression and chemoresistance. Created with BioRender. • Pancreatic cancer (PC) is highly dependent on intracellular cholesterol for survival and evasion of chemotherapeutics. • PC exhibits altered cholesterol homeostasis via increased cholesterol biosynthesis, uptake and storage, and reduced export. • Statins and cyclodextrins serve as potential anticancer agents in PC due to their cholesterol-lowering effects. • Cholesterol-dependent cancers can use alternative mechanisms to sustain cholesterol levels.
Daya et al. (Wed,) studied this question.