The role of cholesterol and cholesterol-driven membrane raft domains in prostate cancer

Abstract

Membrane rafts are heterogeneous and dynamic domains that are characterized by tight packing of lipids. They are enriched in cholesterol, sphingolipids, and certain types of proteins. Among these are various cell signaling proteins, which indicate that rafts play an important role in cell signal transduction pathways, including some involved in cancer development, progression, and invasiveness. Due to their increased cholesterol content, raft domains exhibit lower fluidity than the surrounding membrane. The cell membranes of some solid tumors, such as breast and prostate cancer, contain higher levels of cholesterol, which means larger raft domain can form in those membranes. This may stimulate signaling pathways to promote tumor growth and progression. This review focuses on the known raft-dependent regulatory mechanisms that promote prostate cancer progression.

Impact statement: Prostate cancer remains the most common malignancy and second most frequent cause of cancer-related death in men. Cholesterol levels are usually higher in prostate cancer cells. This affects the cell membrane composition, with cholesterol and sphingolipid-containing raft membrane domains becoming a greater component. In addition to polar lipids, these domains recruit and regulate certain types of protein, including various cell signaling proteins that are critical to cancer cell survival and invasiveness. This suggests that membrane rafts have a regulatory role in tumor progression, making them a potential target in prostate cancer treatment.

Keywords: Cholesterol; caveolae; membrane raft domains; prostate cancer; signaling pathways.

Figure 1.

Caveolar and flat membrane raft-mediated pathways in prostate cancer cells. (a) Signaling pathways that promote prostate tumor growth and progression. (b) LXR as a modulator of membrane raft signaling promoting apoptosis in prostate cancer cells. ABCA1: ATP-binding cassette A1 transporter; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: receptor for CXCL12; EGF: epidermal growth factor; EMT: epithelial-mesenchymal transition; ERK 1/2: extracellular signal regulated kinase 1 and 2; FL1 and FL2: flotillins 1 and 2; HDL: high density lipoprotein; HGF: hepatocyte growth factor; JAK1: Janus kinase 1; JAK2: Janus kinase 2; LXR: liver X receptor; MEK: mitogen activated kinase; MMP9: matrix metalloproteinase 9; NFκB: nuclear factor kappa B; Ptc and Smo: patched and smoothened receptor complex; Shh: sonic hedgehog.