Cholesterol in the ciliary membrane as a therapeutic target against cancer

Abstract

Primary cilium is a non-motile, antenna-like structure that develops in the quiescent G₀ phase-cell surface. It is composed of an array of axonemal microtubules polymerized from the centrosome/basal body. The plasma membrane surrounding the primary cilium, which is called the ciliary membrane, contains a variety of receptors and ion channels, through which the cell receives extracellular chemical and physical stimuli to initiate signal transduction. In general, primary cilia disappear when cells receive the proliferative signals to re-enter the cell cycle. Primary cilia thus cannot be identified in many malignant and proliferative tumors. In contrast, some cancers, including basal cell carcinoma, medulloblastoma, gastrointestinal stromal tumor, and other malignancies, retain their primary cilia. Importantly, it has been reported that the primary cilia-mediated oncogenic signals of Hedgehog, Wnt, and Aurora kinase A are involved in the tumorigenesis and tumor progression of basal cell carcinoma and some types of medulloblastoma. It has also been demonstrated that cholesterol is significantly more enriched in the ciliary membrane than in the rest of the plasma membrane to ensure Sonic hedgehog signaling. A series of epidemiological studies on statin drugs (cholesterol-lowering medication) demonstrated that they prevent recurrence in a wide range of cancers. Taken together, ciliary cholesterol could be a potential therapeutic target in primary cilia-dependent progressive cancers.

Keywords: Wnt signal; cancers; cholesterol; primary cilia; sonic hedgehog signal.

FIGURE 1

Schematic longitudinal section and cholesterol imaging of a primary cilium. (Left) The mother central body (MC) and daughter central bodies (DC) of the basal body (centrosome) are located at the base of the primary cilium, and microtubular axonemes develop from the mother central body docked to the cell membrane. The ciliary membrane covering the axonemes is rich in cholesterol and sphingolipids. At the base of the primary cilia, the plasma membrane is concave, forming a serial pocket. At the transition zone (TZ), the cytoplasm and ciliary membrane of primary cilia are biochemically compartmentalized from other cytoplasmic and cell membranes. (Right) Imaging of ciliary cholesterol in quiescent G₀-phase hTERT-RPE1 cells stained with Filipin III. They were also immunostained with anti-acetylated-tubulin and anti-pericentrin antibodies. The merged image indicates the enriched ciliary cholesterol. Scale bar, 5 μm.

FIGURE 2

Ciliary cholesterol-mediated signal transduction. (Left) In the presence of Shh ligands, Ptch exits from ciliary membrane, while Smo enters and is then activated. Ciliary Smo allows Sufu to release Gli. Activated Gli is translocated into the nucleus, thereby controlling the transcription of Shh responsive genes. Ciliary cholesterol directly binds to Smo to ensure the activation. (Right) In the presence of Wnt1 class ligands, Frizzled-LRP5/6 activates DVL that destabilizes the destruction complex composed of APC and GSK3, thereby allowing β-catenin cytosolic accumulation and nuclear translocation to regulate the Wnt responsive gene expression.