Posted by Pancreatic cancer (PC) 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. The authors 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.
Inhibiting cholesterol synthesis within PC cells does not necessarily improve expected therapeutic outcomes due to a complex interplay of cholesterol storage, influx, efflux pathways that simultaneously influence compensatory cholesterol signalling cascades. The consequences of cholesterol synthesis inhibition may provoke compensatory responses in PC cells
Statins and cyclodextrins serve as potential anticancer agents in pancreatic cancer due to their cholesterol-lowering effects.
Higher amounts of membrane cholesterol are known to be responsible for a more rigid and less permeable membrane thus contributing to chemoresistance in cancer, including PC. Reducing cholesterol levels via β-CDs may thus serve as a method of reducing chemoresistance, as well as preventing PC progression by regulating aberrant cholesterol homeostasis. Unlike other cancer types, there are no studies investigating the effects of CDs on PC progression and chemoresistance via cholesterol depletion alone.
Due to the inconclusive effects observed in the use of statins and CDs as anti-cancer therapeutics, further research is still required. It also remains to be seen if CDs elicit similar response in PC, as observed with statins. Existing literature also suggest a caution that must be taken into consideration while prescribing cholesterol-lowering agents to PC patients due to strong compensatory responses that may counteract desirable effects and thus, there are many open questions in PC research that need to be addressed to create a holistic understanding of the role of cholesterol, which may pave the way for novel therapeutic combinations striving to attenuate PC fatalities.
Tasvi Daya, Andrea Breytenbach, Liang Gu, Mandeep Kaur (2025) Cholesterol metabolism in pancreatic cancer and associated therapeutic strategies. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids 1870, 159578. https://doi.org/10.1016/j.bbalip.2024.159578.