Cilia and cilia-associated proteins in cancer

Abstract

The primary cilium is a well-established target in the pathogenesis of numerous developmental and chronic disorders, and more recently is attracting interest as a structure relevant to cancer. Here we discuss mechanisms by which changes in cilia can contribute to the formation and growth of tumors. We emphasize the cancer-relevance of cilia-dependent signaling pathways and proteins including mTOR, VHL, TSC, WNT, Aurora-A, NEDD9, and Hedgehog, and highlight the emerging role of ciliary dysfunction in renal cell carcinoma, medulloblastoma, and breast cancer.

Figure 1. Cilia-associated hallmarks of transformed epithelial cells

Left panel: The integrity of cell junctions, planar cell polarity (PCP), composition of the extracellular matrix (ECM), proliferation and oriented cell division, and sensing of some soluble extracellular signals are important features for the homeostasis of epithelial cells. Right panel: Loss of cilia is associated with loss of PCP, hyperproliferation, disoriented cell division, disrupted cell junctions, and fibrosis. Together, these defects are important hallmarks of the formation of solid tumors.

Figure 2. Cilia-associated signaling pathways relevant to cancer

A. NEDD9 and AURKA at the basal body initiate ciliary disassembly through the activation of HDAC6 and other substrates. Ca²⁺-liganded CALM and a PLK1-DVL2 complex support the activation of AURKA, while BUBR1 limits DVL2 expression during ciliogenesis. Altered function of AURKA, NEDD9, PLK1 and BUBR1 contributes to oncogenesis by targeting cell cycle progression and other cellular processes. HDAC6, histone deacetylase 6; PLK1, polo-like kinase 1; DVL2, dishevelled-2; AURKA, aurora-A kinase; NEDD9, neural precursor expressed downregulated in development 9; BUBR1, budding uninhibited by benzimidazoles 1-related protein kinase; CALM, calmodulin. B. Renal fluid flow activates ciliary LKB1, which signals through AMPK and the TSC1/TSC2 heterodimer to limit mTOR signaling and cell growth. Ablation of the cilium stimulates cell growth by relieving mTOR inhibition. LKB1 negatively regulates NEDD9; TSC2 limits PLK1. LKB1, liver kinase B1 (also known as serine/threonine-protein kinase STK11); AMPK, 5′-AMP-activated protein kinase; TSC1, hamartin; TSC2, tuberin; mTOR, mammalian target of rapamycin. C. LKB1 signaling to AMPK is in part mediated through the activity of SREBPs, which regulate ciliary stability and activate FASN. Active FASN modifies and alters activity of the ciliary-responsive protein WNT, influencing activity of cytosolic β-catenin, NEDD9, and other oncogenic proteins. SREBP1, sterol regulatory element-binding protein 1; FASN, fatty acid synthase. D. In the presence of oxygen, VHL degrades HIFα; during hypoxia, HIFα induces transcription of angiogenesis promoting factors including VEGF, PDGF, and EPO, as well as NEDD9 and AURKA. VHL in cooperation with PTEN and GSK3 maintains the cilium by stabilizing and orienting microtubules (MT). Additional functions of VHL include the regulation of cell junctions and ECM composition. The depletion of VHL can drive oncogenesis via these various cell processes. GSK3, glycogen synthase kinase 3; PTEN, phosphatase and tensin homolog; VHL, von Hippel-Lindau; HIFα, hypoxia-inducible factor alpha; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor; EPO, erythropoietin.

Figure 3. Targeted therapies in renal cell carcinoma (RCC)

Inactivation of VHL in RCC cells triggers a cascade of signaling and HIFα-dependent transcription that promote tumor growth cell autonomously, and by influencing angiogenesis in adjacent endothelial cells. Drugs currently approved in the therapy of RCC interfere with the downstream effectors of HIFα, including VEGF (bevacizumab), receptor tyrosine kinases (RTKs) like VEGFR and PDGFR (sunitinib, sorafenib, pazopanib, axitinib), and the m-TOR pathway (temsirolimus, everolimus). Ongoing preclinical studies suggest further potential targets with some of them overlapping with the potential targets in the treatment of ciliopathies such as polycystic kidney disease (green). These targets include mTOR, SRC, STAT and the RAS/RAF/MEK/ERK pathway. VEGF(R), vascular endothelial growth factor (receptor); PDGF(R), platelet derived growth factor (receptor); IGF(R), insulin-like growth factor (receptor); ANG-4, angiopoetin-4; TGFα, transforming growth factor alpha; JMJD1A/JMJD2B, jumonji domain-containing protein 1A/2B; JARID1B, lysine-specific demethylase 5B; LDH, lactate dehydrogenase A chain; c-MET, hepatocyte growth factor receptor; ROR2, RTK-like orphan receptor 2; MMP2, matrix metalloproteinase-2; IL6R, interleukin-6 receptor; STAT3, signal transducer and activator of transcription 3; HGF, hepatocyte growth factor; EGFR, epidermal growth factor receptor; TIE2, Tyrosine-protein kinase receptor-2; PI3K, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase kinase 1; ERK, extracellular-regulated kinase; PLCγ phospholipase C-gamma; NO, nitric oxide; PKC, protein kinase C.