The primary cilium: Its role as a tumor suppressor organelle

Abstract

The primary cilium is an organelle that nearly all cells within the body contain. Its function is to sense the extracellular environment through its abundance of receptors and linked signaling pathways, working as an antenna. Ciliary defects lead to different pathologies. In particular, many tumors lose primary cilia, and this is linked with negative implications for the cell such as an increase in malignancy. In this work we will go through the knowledge of the role of primary cilia in normal conditions, how it is involved in diverse signaling pathways, and in disease, particularly in cancer, highlighting its tumor suppressor properties.

Keywords: Cancer; HDAC6; Primary cilia.

Figure 1.. Primary cilium, receptors and signaling pathways.

A. Illustration of transversal plane of primary and motile cilia. Primary cilia have a 9+0 microtubule arrangement while motile cilia contain a 9+2 arrangement and have dynein. B. The primary cilia sense the extracellular environment through its multiple ciliary receptors that results in activation or inhibition of different signaling pathways. LKB1: liver kinase B1; P2YR: Purinergic receptors; PC-1: polycystin-1; PC-2: polycystin-2; PDGFRα: Platelet-derived growth factor receptor α; PTCH: patched receptor; SMO: Smoothened receptor; TGR5: G-protein-coupled bile acid receptor 1; TRPV4: Transient Receptor Potential Vanilloid 4.

Figure 2.. Signaling pathways.

A. Hedgehog signaling. In absence of Hg ligands PTCH accumulates in the cilia and inhibits the entrance of SMO. SuFu binds to Gli proteins inhibiting its transcription factor function. The partial proteolysis of Gli3 produces a repressor form that inhibit the expression of Hg targets. In presence of Hg ligands (i.e. Shh) occurs the activation of PTCH inducing its degradation. Without PTCH, SMO can accumulate in the cilia preventing the degradation of Gli proteins. The Gli proteins can translocate to the nucleus and activate target gene expression. B. Wnt signaling. In the canonical pathway, β-catenin is degraded by a protein complex that includes Apc and Axin. With the activation of the Frizzled receptor the destruction complex is inhibited by the disheveled protein resulting in the stabilization of β-catenin, its translocation to the nucleus and the activation of the expression of target genes. The non-canonical way is involved on the establishment of cell polarity through small GTPases activation. Inversin has a switch role between the canonical and non-canonical pathway. C. Tyrosine kinases signaling. PDGFRα colocalizes in the cilia. The activation transduces in the activation of MEK1/2, AKT (trough the activation of PI3K) and ERK1/2 resulting in cell cycle entry.

Figure 3.. Working model.

Primary cilia function as a sensor of external stimuli into internal signaling pathways with tumor suppressor characteristics. The cholangiocarcinoma malignant transformation includes loss of cilia and derepression of tumorigenic pathways. The targeting of HDAC6 would be a potential treatment approach or ciliotherapy.