{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T03:30:47Z","timestamp":1790652647768,"version":"4.1.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Primary cilium is a non-motile, antenna-like structure that develops in the quiescent G<jats:sub>0<\/jats:sub> 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.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1160415","type":"journal-article","created":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T06:01:17Z","timestamp":1678946477000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Cholesterol in the ciliary membrane as a therapeutic target against cancer"],"prefix":"10.3389","volume":"10","author":[{"given":"Sotai","family":"Kimura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoka","family":"Morita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Hosoba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Itoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuo","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/s42003-021-02118-w","article-title":"Wnt signaling in lung development, regeneration, and disease progression","volume":"4","author":"Aros","year":"2021","journal-title":"Commun. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4967","DOI":"10.1158\/0008-5472.CAN-14-1666","article-title":"Sonic hedgehog signaling in Basal cell nevus syndrome","volume":"74","author":"Athar","year":"2014","journal-title":"Cancer Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1093\/carcin\/bgt041","article-title":"Kif3a is necessary for initiation and maintenance of medulloblastoma","volume":"34","author":"Barakat","year":"2013","journal-title":"Carcinogenesis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/2046-2530-2-6","article-title":"Functional aspects of primary cilia in signaling, cell cycle and tumorigenesis","volume":"2","author":"Basten","year":"2013","journal-title":"Cilia"},{"key":"B5","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1186\/s13058-018-1066-z","article-title":"Statin drugs to reduce breast cancer recurrence and mortality","volume":"20","author":"Beckwitt","year":"2018","journal-title":"Breast Cancer Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e23834","DOI":"10.1371\/journal.pone.0023834","article-title":"The hedgehog receptor patched is involved in cholesterol transport","volume":"6","author":"Bidet","year":"2011","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/nature18934","article-title":"Structural basis of Smoothened regulation by its extracellular domains","volume":"535","author":"Byrne","year":"2016","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1111\/jcmm.12067","article-title":"Primary cilia in gastric gastrointestinal stromal tumours (GISTs): An ultrastructural study","volume":"17","author":"Castiella","year":"2013","journal-title":"J. Cell Mol. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1016\/j.it.2018.08.006","article-title":"Canonical and non-canonical Wnt signaling in immune cells","volume":"39","author":"Chae","year":"2018","journal-title":"Trends Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e141171","DOI":"10.1172\/JCI141171","article-title":"Smoothened-activating lipids drive resistance to CDK4\/6 inhibition in Hedgehog-associated medulloblastoma cells and preclinical models","volume":"131","author":"Daggubati","year":"2021","journal-title":"J. Clin. Invest"},{"key":"B11","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/s41586-019-1355-4","article-title":"Smoothened stimulation by membrane sterols drives Hedgehog pathway activity","volume":"571","author":"Deshpande","year":"2019","journal-title":"Nature"},{"key":"B12","first-page":"1233","article-title":"Prognostic significance of the frequency of primary cilia in cells of small bowel and colorectal adenocarcinoma","volume":"21","author":"Dvorak","year":"2016","journal-title":"J. BUON"},{"key":"B13","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/j.humpath.2013.11.017","article-title":"Presence of primary cilia in cancer cells correlates with prognosis of pancreatic ductal adenocarcinoma","volume":"45","author":"Emoto","year":"2014","journal-title":"Hum. Pathol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.3390\/ijms20061336","article-title":"Primary cilium in cancer hallmarks","volume":"20","author":"Fabbri","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"9151","DOI":"10.1073\/pnas.1323265111","article-title":"Primary cilia control hedgehog signaling during muscle differentiation and are deregulated in rhabdomyosarcoma","volume":"111","author":"Fu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B16","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s10549-009-0507-x","article-title":"Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer","volume":"119","author":"Garwood","year":"2010","journal-title":"Breast Cancer Res. Treat."},{"key":"B17","doi-asserted-by":"publisher","first-page":"E10532","DOI":"10.1073\/pnas.1711534114","article-title":"EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling","volume":"114","author":"Guen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"B18","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.cell.2004.07.024","article-title":"Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities","volume":"118","author":"Harfe","year":"2004","journal-title":"Cell"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/cells8111380","article-title":"Wnt Signaling in the Regulation of Immune Cell and Cancer Therapeutics","volume":"8","author":"Haseeb","year":"2019","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1158\/1078-0432.CCR-11-0755","article-title":"Molecular pathways: The role of primary cilia in cancer progression and therapeutics with a focus on hedgehog signaling","volume":"18","author":"Hassounah","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e68521","DOI":"10.1371\/journal.pone.0068521","article-title":"Primary cilia are lost in preinvasive and invasive prostate cancer","volume":"8","author":"Hassounah","year":"2013","journal-title":"PLoS One"},{"key":"B21","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1186\/s40880-015-0052-4","article-title":"Wnt3a: Functions and implications in cancer","volume":"34","author":"He","year":"2015","journal-title":"Chin. J. Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.cell.2018.09.003","article-title":"Structural basis of smoothened activation in hedgehog signaling","volume":"175","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13630-015-0021-1","article-title":"Current topics of functional links between primary cilia and cell cycle","volume":"4","author":"Izawa","year":"2015","journal-title":"Cilia"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.2147\/OTT.S130910","article-title":"Sonidegib: Mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas","volume":"10","author":"Jain","year":"2017","journal-title":"Onco Targets Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1186\/s13046-021-02041-2","article-title":"Statins: A repurposed drug to fight cancer","volume":"40","author":"Jiang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"8087","DOI":"10.1038\/ncomms.9087","article-title":"Nek2 activation of Kif24 ensures cilium disassembly during the cell cycle","volume":"6","author":"Kim","year":"2015","journal-title":"Nat. Commun."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e50051","DOI":"10.7554\/eLife.50051","article-title":"Cholesterol accessibility at the ciliary membrane controls hedgehog signaling","volume":"8","author":"Kinnebrew","year":"2019","journal-title":"Elife"},{"key":"B28","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.devcel.2010.06.005","article-title":"Pitchfork regulates primary cilia disassembly and left-right asymmetry","volume":"19","author":"Kinzel","year":"2010","journal-title":"Dev. Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.jid.2018.11.035","article-title":"Loss of primary cilia drives switching from hedgehog to ras\/MAPK pathway in resistant basal cell carcinoma","volume":"139","author":"Kuonen","year":"2019","journal-title":"J. Invest Dermatol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"4181","DOI":"10.1038\/s41598-021-83418-3","article-title":"Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer","volume":"11","author":"Lee","year":"2021","journal-title":"Sci. Rep."},{"key":"B31","doi-asserted-by":"publisher","first-page":"5027","DOI":"10.1111\/febs.15579","article-title":"Involvement of Wnt signaling in primary cilia assembly and disassembly","volume":"287","author":"Lee","year":"2020","journal-title":"FEBS J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/s41568-018-0023-6","article-title":"Ciliary signalling in cancer","volume":"18","author":"Liu","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"5202750","DOI":"10.1155\/2019\/5202750","article-title":"Primary cilia blockage promotes the malignant behaviors of hepatocellular carcinoma via induction of autophagy","volume":"2019","author":"Liu","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"B34","doi-asserted-by":"publisher","first-page":"5791","DOI":"10.1158\/1078-0432.CCR-20-1967","article-title":"Statins as anticancer agents in the era of precision medicine","volume":"26","author":"Longo","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1101\/gad.349856.122","article-title":"Subgroup-specific roles of primary cilia in medulloblastoma","volume":"36","author":"Marino","year":"2022","journal-title":"Genes Dev."},{"key":"B36","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/978-3-642-54490-3_25","article-title":"Vismodegib","volume":"201","author":"Meiss","year":"2014","journal-title":"Recent Results Cancer Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/978-1-0716-1701-4_5","article-title":"Imaging of the ciliary cholesterol underlying the sonic hedgehog signal transduction","volume":"2374","author":"Miyamoto","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"e103499","DOI":"10.15252\/embj.2019103499","article-title":"Insufficiency of ciliary cholesterol in hereditary Zellweger syndrome","volume":"39","author":"Miyamoto","year":"2020","journal-title":"EMBO J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.celrep.2015.01.003","article-title":"The microtubule-depolymerizing activity of a mitotic kinesin protein KIF2A drives primary cilia disassembly coupled with cell proliferation","volume":"10","author":"Miyamoto","year":"2015","journal-title":"Cell Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1038\/nchembio.1290","article-title":"Oxysterol binding to the extracellular domain of Smoothened in Hedgehog signaling","volume":"9","author":"Nedelcu","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"147","DOI":"10.3390\/cells8020147","article-title":"Gli proteins: Regulation in development and cancer","volume":"8","author":"Niewiadomski","year":"2019","journal-title":"Cells"},{"key":"B42","doi-asserted-by":"publisher","first-page":"210130","DOI":"10.1098\/rsob.210130","article-title":"Primary cilia and lipid raft dynamics","volume":"11","author":"Nishimura","year":"2021","journal-title":"Open Biol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1111\/gtc.12122","article-title":"Absence of primary cilia in cell cycle-arrested human breast cancer cells","volume":"19","author":"Nobutani","year":"2014","journal-title":"Genes cells."},{"key":"B44","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/s42003-021-02054-9","article-title":"ARP-T1-associated Bazex-Dupre-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies","volume":"4","author":"Park","year":"2021","journal-title":"Commun. Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"50","DOI":"10.3390\/cancers8050050","article-title":"Frizzled7: A promising achilles' heel for targeting the Wnt receptor complex to treat cancer","volume":"8","author":"Phesse","year":"2016","journal-title":"Cancers (Basel)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.cell.2007.04.035","article-title":"HEF1-dependent Aurora A activation induces disassembly of the primary cilium","volume":"129","author":"Pugacheva","year":"2007","journal-title":"Cell"},{"key":"B47","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41586-018-0308-7","article-title":"Structures of human Patched and its complex with native palmitoylated sonic hedgehog","volume":"560","author":"Qi","year":"2018","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.molcel.2018.08.034","article-title":"Cilia-associated oxysterols activate smoothened","volume":"72","author":"Raleigh","year":"2018","journal-title":"Mol. Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"a002014","DOI":"10.1101\/cshperspect.a002014","article-title":"Establishing and interpreting graded sonic hedgehog signaling during vertebrate neural tube patterning: The role of negative feedback","volume":"1","author":"Ribes","year":"2009","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.molcel.2019.09.008","article-title":"Even cancer cells watch their cholesterol","volume":"76","author":"Riscal","year":"2019","journal-title":"Mol. Cell"},{"key":"B51","first-page":"1644","article-title":"Negative prognostic significance of primary cilia, CD8+ tumor infiltrating lymphocytes and PD1+ cells expression in clear cell renal cancer","volume":"24","author":"Rozsypalova","year":"2019","journal-title":"J. BUON"},{"key":"B52","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1158\/0008-5472.CAN-08-1290","article-title":"Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia","volume":"69","author":"Seeley","year":"2009","journal-title":"Cancer Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"4393","DOI":"10.1038\/ncomms5393","article-title":"Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling","volume":"5","author":"Sheng","year":"2014","journal-title":"Nat. Commun."},{"key":"B54","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1126\/science.1124534","article-title":"The primary cilium as the cell's antenna: Signaling at a sensory organelle","volume":"313","author":"Singla","year":"2006","journal-title":"Science"},{"key":"B55","doi-asserted-by":"publisher","first-page":"a007963","DOI":"10.1101\/cshperspect.a007963","article-title":"Wnt signaling in mammalian development: Lessons from mouse genetics","volume":"4","author":"Wang","year":"2012","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"864035","DOI":"10.3389\/fcell.2022.864035","article-title":"Sonic hedgehog signaling in cerebellar development and cancer","volume":"10","author":"Wang","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"B57","volume-title":"Central nervous system tumours","year":"2021"},{"key":"B58","doi-asserted-by":"publisher","first-page":"eabf6063","DOI":"10.1126\/sciadv.abf6063","article-title":"An EMT-primary cilium-GLIS2 signaling axis regulates mammogenesis and claudin-low breast tumorigenesis","volume":"7","author":"Wilson","year":"2021","journal-title":"Sci. Adv."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e19596","DOI":"10.1097\/MD.0000000000019596","article-title":"Impact of statin use on cancer-specific mortality and recurrence: A meta-analysis of 60 observational studies","volume":"99","author":"Yang","year":"2020","journal-title":"Med. Baltim."},{"key":"B60","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1101\/gad.349596.122","article-title":"Primary cilia control translation and the cell cycle in medulloblastoma","volume":"36","author":"Youn","year":"2022","journal-title":"Genes Dev."},{"key":"B61","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.devcel.2022.12.006","article-title":"Primary cilia are WNT-transducing organelles whose biogenesis is controlled by a WNT-PP1 axis","volume":"58","author":"Zhang","year":"2023","journal-title":"Dev. Cell"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2023.1160415\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T06:01:20Z","timestamp":1678946480000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2023.1160415\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,16]]},"references-count":62,"alternative-id":["10.3389\/fmolb.2023.1160415"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2023.1160415","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,16]]},"article-number":"1160415"}}