The Role of Oxysterols in Human Cancer

Abstract

Oxysterols are oxygenated derivatives of cholesterol formed in the human body or ingested in the diet. By modulating the activity of many proteins [e.g., liver X receptors (LXRs), oxysterol-binding proteins (OSBPs), some ATP-binding cassette (ABC) transporters], oxysterols can affect many cellular functions and influence various physiological processes (e.g., cholesterol metabolism, membrane fluidity regulation, intracellular signaling pathways). Therefore, the role of oxysterols is also important in pathological conditions (e.g., atherosclerosis, diabetes mellitus type 2, neurodegenerative disorders). Finally, current evidence suggests that oxysterols play a role in malignancies such as breast, prostate, colon, and bile duct cancer. This review summarizes the physiological importance of oxysterols in the human body with a special emphasis on their roles in various tumors.

Keywords: cancer; cholesterol; disease; oxysterols.

Figure 1. Structures of common oxysterols

Oxysterols are formed by both enzymatic and non-enzymatic reactions. The enzymatic pathways are mediated by enzymes from the cytochrome P450 (CYP) family and cholesterol-25-hydroxylase (CH25H). Enzymatic oxidation of cholesterol gives rise to side-chain oxysterols (blue), and ring-oxysterols are generated by non-enzymatic oxidation mediated by reactive oxygen species (ROS, red). Some oxysterols are generated by both enzymatic and non-enzymatic reactions (purple).

Figure 2. The role of oxysterols in physiological cellular processes

Oxysterols are important regulators of many biological processes in the cell. The regulation of sterol metabolism is mediated by various ways – through transcription factors (liver X receptors - LXRs, or sterol regulatory binding proteins - SREBPs), by interaction with oxysterol-binding proteins - OSBPs, or by regulation of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, a key enzyme of cholesterol metabolism. Oxysterols influence the biophysical properties of lipid membranes, such as the ordering of the bilayer [4] and play role in vesicular transport. Oxysterols also interact with integral or peripheral membrane proteins and are capable of modulation of their activity. They modulate the activity, e.g., of ABC transporters, or Na⁺/K⁺ ATPase. Oxysterols also interact with signaling pathway proteins and may modulate the Hedgehog, Wnt, or MAP kinase signaling.

Figure 3. The role of oxysterols in carcinogenesis and modulation of cell proliferation

The model of pro-apoptotic and pro-cancerous role of oxysterols is adapted from the proposed scheme of cholangiocarcinogenesis by Jusakul et al.,[58], suggesting that this model could be applied also to other cancers. The scheme is specifically focused on oxysterol effects in breast carcinoma where oxysterols can interfere with hormonal therapy by binding to anti-estrogen binding sites (AEBS) and estrogen receptor (ER) molecules. The anti-proliferative and pro-apoptotic action of oxysterols is marked by blue rectangles and the pro-proliferative and pro-cancerous effect by red ones.