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Pant K, Peixoto E, Gradilone SA. Primary Cilia in Hepatic Biliary Hyperplasia: Implications for Liver Diseases. Semin Liver Dis 2025. [PMID: 40118103 DOI: 10.1055/a-2563-9791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/23/2025]
Abstract
Primary cilia, hair-like projections on the surface of various cell types, play crucial roles in sensing and regulating environmental cues within the liver, particularly among cholangiocytes. These structures detect changes in bile composition, flow, and other biochemical signals, integrating this information to modulate cellular processes. Dysfunction in cholangiocyte cilia-whether due to structural abnormalities or genetic mutations-has been linked to an array of cholangiopathies and ciliopathies. These include conditions such as biliary atresia, cholangiocarcinoma, primary sclerosing cholangitis, and polycystic liver diseases, each with distinct clinical phenotypes influenced by impaired ciliary function. Given the complexity of the ciliary proteome and its role in cellular signaling, including the Hedgehog, Wnt, and TGR5 pathways, ciliary dysfunction disrupts essential signaling cascades, thus driving disease progression. While over 40 gene mutations are associated with ciliopathic features, there may be additional contributors within the expansive ciliary proteome. This study synthesizes current knowledge on cholangiocyte cilia, emphasizing their mechanistic role in liver disease, and highlights emerging therapeutic strategies aimed at restoring ciliary function. In conclusion, ciliotherapies are proposed as a promising approach for addressing cholangiopathies, with the potential to shift the current therapeutic landscape.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, Minnesota
| | | | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin, Minnesota
- Masonic Cancer Centre, University of Minnesota, Minneapolis, Minnesota
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2
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Quelhas P, Morgado D, dos Santos J. Primary Cilia, Hypoxia, and Liver Dysfunction: A New Perspective on Biliary Atresia. Cells 2025; 14:596. [PMID: 40277920 PMCID: PMC12026149 DOI: 10.3390/cells14080596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/02/2025] [Accepted: 04/11/2025] [Indexed: 04/26/2025] Open
Abstract
Ciliopathies are disorders that affect primary or secondary cellular cilia or structures associated with ciliary function. Primary cilia (PC) are essential for metabolic regulation and embryonic development, and pathogenic variants in cilia-related genes are linked to several pediatric conditions, including renal-hepatic diseases and congenital defects. Biliary atresia (BA) is a progressive infantile cholangiopathy and the leading cause of pediatric liver transplantation. Although the exact etiology of BA remains unclear, evidence suggests a multifactorial pathogenesis influenced by both genetic and environmental factors. Patients with BA and laterality defects exhibit genetic variants associated with ciliopathies. Interestingly, even isolated BA without extrahepatic anomalies presents morphological and functional ciliary abnormalities, suggesting that environmental triggers may disrupt the ciliary function. Among these factors, hypoxia has emerged as a potential modulator of this dysfunction. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a central role in hepatic responses to oxygen deprivation, influencing bile duct remodeling and fibrosis, which are key processes in BA progression. This review explores the crosstalk between hypoxia and hepatic ciliopathies, with a focus on BA. It discusses the molecular mechanisms through which hypoxia may drive disease progression and examines the therapeutic potential of targeting hypoxia-related pathways. Understanding how oxygen deprivation influences ciliary function may open new avenues for treating biliary ciliopathies and improving patient outcomes.
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Affiliation(s)
| | | | - Jorge dos Santos
- RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; (P.Q.); (D.M.)
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Pant K, Richard S, Peixoto E, Baral S, Yang R, Ren Y, Masyuk TV, LaRusso NF, Gradilone SA. Cholangiocyte ciliary defects induce sustained epidermal growth factor receptor signaling. Hepatology 2025; 81:1132-1145. [PMID: 39186465 DOI: 10.1097/hep.0000000000001055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 07/29/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND AND AIMS The primary cilium, an organelle that protrudes from cell surfaces, is essential for sensing extracellular signals. With disturbed cellular communication and chronic liver pathologies, this organelle's dysfunctions have been linked to disorders, including polycystic liver disease and cholangiocarcinoma. The goal of this study was to elucidate the relationship between primary cilia and the crucial regulator of cellular proliferation, the epidermal growth factor receptor (EGFR) signaling pathway, which has been associated with various clinical conditions. APPROACH AND RESULTS The study identified aberrant EGFR signaling pathways in cholangiocytes lacking functional primary cilia using liver-specific intraflagellar transport 88 knockout mice, a Pkhd1 mutant rat model, and human cell lines that did not have functional cilia. Cilia-deficient cholangiocytes showed persistent EGFR activation because of impaired receptor degradation, in contrast to their normal counterparts, where EGFR localization to the cilia promotes appropriate signaling. Using histone deacetylase 6 inhibitors to restore primary cilia accelerates EGFR degradation, thereby reducing maladaptive signaling. Importantly, experimental intervention with the histone deacetylase 6 inhibitor tubastatin A in an orthotopic rat model moved EGFR to cilia and reduced ERK phosphorylation. Concurrent administration of EGFR and histone deacetylase 6 inhibitors in cholangiocarcinoma and polycystic liver disease cells demonstrated synergistic antiproliferative effects, which were associated with the restoration of functioning primary cilia. CONCLUSIONS This study's findings shed light on ciliary function and robust EGFR signaling with slower receptor turnover. We could use therapies that restore the function of primary cilia to treat EGFR-driven diseases in polycystic liver disease and cholangiocarcinoma.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
| | - Seth Richard
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
| | | | - Subheksha Baral
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
| | - Rendong Yang
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Yanan Ren
- Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Tatyana V Masyuk
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin, Minnesota, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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Roth C, Paulini L, Hoffmann ME, Mosler T, Dikic I, Brunschweiger A, Körschgen H, Behl C, Linder B, Kögel D. BAG3 regulates cilia homeostasis of glioblastoma via its WW domain. Biofactors 2024; 50:1113-1133. [PMID: 38655699 PMCID: PMC11627473 DOI: 10.1002/biof.2060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/27/2024] [Indexed: 04/26/2024]
Abstract
The multidomain protein BAG3 exerts pleiotropic oncogenic functions in many tumor entities including glioblastoma (GBM). Here, we compared BAG3 protein-protein interactions in either adherently cultured or stem-like cultured U251 GBM cells. In line with BAG3's putative role in regulating stem-like properties, identified interactors in sphere-cultured cells included different stem cell markers (SOX2, OLIG2, and NES), while interactomes of adherent BAG3-proficient cells indicated a shift toward involvement of BAG3 in regulation of cilium assembly (ACTR3 and ARL3). Applying a set of BAG3 deletion constructs we could demonstrate that none of the domains except the WW domain are required for suppression of cilia formation by full-length BAG3 in U251 and U343 cells. In line with the established regulation of the Hippo pathway by this domain, we could show that the WW mutant fails to rescue YAP1 nuclear translocation. BAG3 depletion reduced activation of a YAP1/AURKA signaling pathway and induction of PLK1. Collectively, our findings point to a complex interaction network of BAG3 with several pathways regulating cilia homeostasis, involving processes related to ciliogenesis and cilium degradation.
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Affiliation(s)
- Caterina Roth
- Department of Neurosurgery, Experimental NeurosurgeryUniversity Hospital, Goethe UniversityFrankfurt am MainGermany
| | - Lara Paulini
- Department of Neurosurgery, Experimental NeurosurgeryUniversity Hospital, Goethe UniversityFrankfurt am MainGermany
| | | | - Thorsten Mosler
- Institute of Biochemistry II, Goethe UniversityFrankfurt am MainGermany
| | - Ivan Dikic
- Institute of Biochemistry II, Goethe UniversityFrankfurt am MainGermany
- Buchmann Institute for Molecular Life Sciences, Goethe UniversityFrankfurt am MainGermany
| | - Andreas Brunschweiger
- Institute of Pharmacy and Food Chemistry, Faculty of Chemistry and PharmacyJulius‐Maximilians‐UniversitätWürzburgGermany
| | - Hagen Körschgen
- Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Christian Behl
- Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg UniversityMainzGermany
| | - Benedikt Linder
- Department of Neurosurgery, Experimental NeurosurgeryUniversity Hospital, Goethe UniversityFrankfurt am MainGermany
| | - Donat Kögel
- Department of Neurosurgery, Experimental NeurosurgeryUniversity Hospital, Goethe UniversityFrankfurt am MainGermany
- German Cancer Consortium (DKTK), Partner Site FrankfurtFrankfurt am MainGermany
- German Cancer Research Center DKFZHeidelbergGermany
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Nikhil K, Shah K. The significant others of aurora kinase a in cancer: combination is the key. Biomark Res 2024; 12:109. [PMID: 39334449 PMCID: PMC11438406 DOI: 10.1186/s40364-024-00651-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
AURKA is predominantly famous as an essential mitotic kinase. Recent findings have also established its critical role in a plethora of other biological processes including ciliogenesis, mitochondrial dynamics, neuronal outgrowth, DNA replication and cell cycle progression. AURKA overexpression in numerous cancers is strongly associated with poor prognosis and survival. Still no AURKA-targeted drug has been approved yet, partially because of the associated collateral toxicity and partly due to its limited efficacy as a single agent in a wide range of tumors. Mechanistically, AURKA overexpression allows it to phosphorylate numerous pathological substrates promoting highly aggressive oncogenic phenotypes. Our review examines the most recent advances in AURKA regulation and focuses on 33 such direct cancer-specific targets of AURKA and their associated oncogenic signaling cascades. One of the common themes that emerge is that AURKA is often involved in a feedback loop with its substrates, which could be the decisive factor causing its sustained upregulation and hyperactivation in cancer cells, an Achilles heel not exploited before. This dynamic interplay between AURKA and its substrates offers potential opportunities for targeted therapeutic interventions. By targeting these substrates, it may be possible to disrupt this feedback loop to effectively reverse AURKA levels, thereby providing a promising avenue for developing safer AURKA-targeted therapeutics. Additionally, exploring the synergistic effects of AURKA inhibition with its other oncogenic and/or tumor-suppressor targets could provide further opportunities for developing effective combination therapies against AURKA-driven cancers, thereby maximizing its potential as a critical drug target.
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Affiliation(s)
- Kumar Nikhil
- Department of Chemistry, Purdue University Institute for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA.
- School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, 751024, India.
| | - Kavita Shah
- Department of Chemistry, Purdue University Institute for Cancer Research, 560 Oval Drive, West Lafayette, IN, 47907, USA.
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Long X, Chen L, Xiao X, Min X, Wu Y, Yang Z, Wen X. Structure, function, and research progress of primary cilia in reproductive physiology and reproductive diseases. Front Cell Dev Biol 2024; 12:1418928. [PMID: 38887518 PMCID: PMC11180893 DOI: 10.3389/fcell.2024.1418928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 05/16/2024] [Indexed: 06/20/2024] Open
Abstract
Primary cilia, serving as the central hub for cellular signal transduction, possess the remarkable ability to translate diverse extracellular signals, both chemical and mechanical, into intracellular responses. Their ubiquitous presence in the reproductive system underscores their pivotal roles in various cellular processes including development, differentiation, and migration. Emerging evidence suggests primary cilia as key players in reproductive physiology and associated pathologies. Notably, primary cilia have been identified in granulosa cells within mouse ovaries and uterine stromal cells, and perturbations in their structure and function have been implicated in a spectrum of reproductive dysfunctions and ciliary-related diseases. Furthermore, disruptions in primary cilia-mediated signal transduction pathways under pathological conditions exacerbate the onset and progression of reproductive disorders. This review provides a comprehensive overview of current research progress on primary cilia and their associated signaling pathways in reproductive physiology and diseases, with the aim of furnishing theoretical groundwork for the prevention and management of primary cilia-related structural and functional abnormalities contributing to reproductive system pathologies.
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Affiliation(s)
- Xiaochuan Long
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
| | - Li Chen
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
| | - Xinyao Xiao
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
| | - Xiayu Min
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
| | - Yao Wu
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
| | - Zengming Yang
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
- Basic Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
| | - Xin Wen
- Clinical Veterinary Laboratory, College of Animal Science, Guizhou University, Guizhou, China
- Key Laboratory of Animal Genetic, Breeding and Reproduction in the plateau Mountainous Region, Ministry of Education, Guizhou University, Guizhou, China
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Wang HY, Diao Y, Tan PZ, Liang H. Four centrosome-related genes to predict the prognosis and drug sensitivity of patients with colon cancer. World J Gastrointest Oncol 2024; 16:1908-1924. [PMID: 38764831 PMCID: PMC11099447 DOI: 10.4251/wjgo.v16.i5.1908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/08/2024] [Accepted: 02/22/2024] [Indexed: 05/09/2024] Open
Abstract
BACKGROUND As the primary microtubule organizing center in animal cells, centrosome abnormalities are involved in human colon cancer. AIM To explore the role of centrosome-related genes (CRGs) in colon cancer. METHODS CRGs were collected from public databases. Consensus clustering analysis was performed to separate the Cancer Genome Atlas cohort. Univariate Cox and least absolute shrinkage selection operator regression analyses were performed to identify candidate prognostic CRGs and construct a centrosome-related signature (CRS) to score colon cancer patients. A nomogram was developed to evaluate the CRS risk in colon cancer patients. An integrated bioinformatics analysis was conducted to explore the correlation between the CRS and tumor immune microenvironment and response to immunotherapy, chemotherapy, and targeted therapy. Single-cell transcriptome analysis was conducted to examine the immune cell landscape of core prognostic genes. RESULTS A total of 726 CRGs were collected from public databases. A CRS was constructed, which consisted of the following four genes: TSC1, AXIN2, COPS7A, and MTUS1. Colon cancer patients with a high-risk signature had poor survival. Patients with a high-risk signature exhibited decreased levels of plasma cells and activated memory CD4+ T cells. Regarding treatment response, patients with a high-risk signature were resistant to immunotherapy, chemotherapy, and targeted therapy. COPS7A expression was relatively high in endothelial cells and fibroblasts. MTUS1 expression was high in endothelial cells, fibroblasts, and malignant cells. CONCLUSION We constructed a centrosome-related prognostic signature that can accurately predict the prognosis of colon cancer patients, contributing to the development of individualized treatment for colon cancer.
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Affiliation(s)
- Hui-Yan Wang
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin 150086, Heilongjiang Province, China
| | - Yan Diao
- Department of Clinical Laboratory, Heilongjiang Province Hospital, Harbin 150000, Heilongjiang Province, China
| | - Pei-Zhu Tan
- Translational Medicine Center of Northern China, Harbin Medical University, Harbin 150081, Heilongjiang Province, China
| | - Huan Liang
- Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin 150086, Heilongjiang Province, China
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8
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Li Z, Zhao H, Li S, Jiao Z. Midbody remnant regulates the formation of primary cilia and their roles in tumor growth. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:261-268. [PMID: 38413234 PMCID: PMC11057987 DOI: 10.3724/zdxbyxb-2023-0461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/26/2024] [Indexed: 02/29/2024]
Abstract
Recent studies have shown that the formation of the primary cilium is associated with a specific cellular organelle known as the midbody remnant (MBR), which is a point-like organelle formed by shedding of the midbody at the end of mitosis. MBRs move along the cell surface close to the center body and regulate it to form primary cilia at the top of the centriole. Primary cilia can act as an organelle to inhibit tumorigenesis, and it is lost in a variety of tumors. Studies have shown that the accumulation of MBRs in tumor cells affects ciliogenesis; in addition, both MBRs and primary cilia are degraded in tumor cells through the autophagy pathway, and MBRs can also transfer tumor signaling pathway factors to primary cilia affecting tumorigenesis. In this article, the basic structure and the formation process of MBR and primary cilia are reviewed and the mechanism of MBRs regulating ciliogenesis is elaborated. The significance of MBR-mediated ciliogenesis in tumorigenesis and its potential as a target for cancer treatment are discussed.
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Affiliation(s)
- Zhengyang Li
- The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, China.
| | - Huiming Zhao
- The Second Clinical Medical College of Lanzhou University, Lanzhou 730030, China
| | - Subing Li
- College of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China
| | - Zuoyi Jiao
- Department of General Surgery, the Second Hospital of Lanzhou University, Lanzhou 730030, China.
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Ma CX, Ma XN, Liu JJ, Guan CH, Li YD, Zhao N, Mauricio D, Fu SB. The BRAF V600E mutation maintains the aggressiveness of papillary thyroid cancers requiring downregulation of primary cilia. Mol Cell Endocrinol 2024; 581:112113. [PMID: 37989409 DOI: 10.1016/j.mce.2023.112113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/23/2023]
Abstract
Although disorders of primary cilia (PCs) were first reported in human papillary thyroid cancer (PTC) tissues in 1987, their precise role in PTC remains unclear. PCs sense the thyroid follicle colloid environment and act as a cell signaling hub. The present study investigated whether PCs are needed for BRAFV600E-driven PTC. We assessed whether BRAFV600E protein expression correlates with papillary histological architecture and clinicopathological features of PTC. We found that expression of ciliary intraflagellar transport 88 (IFT88) and PC formation were reduced in BRAFV600E-driven PTCs and that loss of cilia may be associated with lymph node metastasis. In PTC cells, the BRAFV600E mutation maintained the aggressiveness of PTC, which was partially related to loss of PCs. Our work confirms that BRAFV600E mutation-driven PC downregulation contributes to maintaining the aggressiveness of PTCs and that manipulating PC can potentially reduce the adverse incidence of PTC in a range of conditions.
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Affiliation(s)
- Cheng-Xu Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Xiao-Ni Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Jin-Jin Liu
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Cong-Hui Guan
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Ying-Dong Li
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, China
| | - Nan Zhao
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China
| | - Dídac Mauricio
- Department of Endocrinology & Nutrition, CIBERDEM, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 08041 Barcelona, Spain.
| | - Song-Bo Fu
- Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, Gansu 730000, China; The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, China.
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10
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Tian Z, Li X, Yu X, Yan S, Sun J, Ma W, Zhu X, Tang Y. The role of primary cilia in thyroid diseases. Front Endocrinol (Lausanne) 2024; 14:1306550. [PMID: 38260150 PMCID: PMC10801159 DOI: 10.3389/fendo.2023.1306550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/05/2023] [Indexed: 01/24/2024] Open
Abstract
Primary cilia (PC) are non-motile and microtube-based organelles protruding from the surface of almost all thyroid follicle cells. They maintain homeostasis in thyrocytes and loss of PC can result in diverse thyroid diseases. The dysfunction of structure and function of PC are found in many patients with common thyroid diseases. The alterations are associated with the cause, development, and recovery of the diseases and are regulated by PC-mediated signals. Restoring normal PC structure and function in thyrocytes is a promising therapeutic strategy to treat thyroid diseases. This review explores the function of PC in normal thyroid glands. It summarizes the pathology caused by PC alterations in thyroid cancer (TC), autoimmune thyroid diseases (AITD), hypothyroidism, and thyroid nodules (TN) to provide comprehensive references for further study.
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Affiliation(s)
- Zijiao Tian
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Xinlin Li
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Xue Yu
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Shuxin Yan
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Jingwei Sun
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Wenxin Ma
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoyun Zhu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yang Tang
- College of Traditional Chinese Medicine of Beijing University of Chinese Medicine, Beijing, China
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Sakaji K, Ebrahimiazar S, Harigae Y, Ishibashi K, Sato T, Yoshikawa T, Atsumi GI, Sung CH, Saito M. MAST4 promotes primary ciliary resorption through phosphorylation of Tctex-1. Life Sci Alliance 2023; 6:e202301947. [PMID: 37726137 PMCID: PMC10509483 DOI: 10.26508/lsa.202301947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 08/27/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023] Open
Abstract
The primary cilium undergoes cell cycle-dependent assembly and disassembly. Dysregulated ciliary dynamics are associated with several pathological conditions called ciliopathies. Previous studies showed that the localization of phosphorylated Tctex-1 at Thr94 (T94) at the ciliary base critically regulates ciliary resorption by accelerating actin remodeling and ciliary pocket membrane endocytosis. Here, we show that microtubule-associated serine/threonine kinase family member 4 (MAST4) is localized at the primary cilium. Suppressing MAST4 blocks serum-induced ciliary resorption, and overexpressing MAST4 accelerates ciliary resorption. Tctex-1 binds to the kinase domain of MAST4, in which the R503 and D504 residues are key to MAST4-mediated ciliary resorption. The ciliary resorption and the ciliary base localization of phospho-(T94)Tctex-1 are blocked by the knockdown of MAST4 or the expression of the catalytic-inactive site-directed MAST4 mutants. Moreover, MAST4 is required for Cdc42 activation and Rab5-mediated periciliary membrane endocytosis during ciliary resorption. These results support that MAST4 is a novel kinase that regulates ciliary resorption by modulating the ciliary base localization of phospho-(T94)Tctex-1. MAST4 is a potential new target for treating ciliopathies causally by ciliary resorption defects.
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Affiliation(s)
- Kensuke Sakaji
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sara Ebrahimiazar
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Harigae
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenichi Ishibashi
- Department of Molecular Physiology and Pathology, School of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan
| | - Takeya Sato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Yoshikawa
- Department of Neuropharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
- Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Gen-Ichi Atsumi
- Department of Molecular Physiology and Pathology, School of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan
| | - Ching-Hwa Sung
- Department of Ophthalmology, Margaret M. Dyson Vision Research Institute, Weill Cornell Medicine, New York, NY, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA
| | - Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Molecular Physiology and Pathology, School of Pharma-Science, Teikyo University, Itabashi-ku, Tokyo, Japan
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Pant K, Venugopal SK, Lorenzo Pisarello MJ, Gradilone SA. The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1455-1467. [PMID: 37422149 PMCID: PMC10548274 DOI: 10.1016/j.ajpath.2023.06.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/10/2023]
Abstract
The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of short-chain fatty acids via the blood flowing from the gut via the portal vein. Butyrate helps prevent nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. It ameliorates metabolic diseases, including insulin resistance and obesity, and plays a direct role in preventing fatty liver diseases. Butyrate has different mechanisms of action, including strong regulatory effects on the expression of many genes by inhibiting the histone deacetylases and modulating cellular metabolism. The present review highlights the wide range of beneficial therapeutic and unfavorable adverse effects of butyrate, with a high potential for clinically important uses in several liver diseases.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, Minnesota.
| | - Senthil K Venugopal
- Laboratory of Molecular Medicine and Hepatology, Faculty of Life Science and Biotechnology, South Asian University, New Delhi, India
| | - Maria J Lorenzo Pisarello
- Laboratory of Immunobiotechnology, Reference Centre for Lactobacilli (CERELA), National Council of Scientific and Technological Research, San Miguel de Tucuman, Argentina; Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
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13
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Saito M, Otsu W, Miyadera K, Nishimura Y. Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets. Front Mol Biosci 2023; 10:1232188. [PMID: 37780208 PMCID: PMC10538646 DOI: 10.3389/fmolb.2023.1232188] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/24/2023] [Indexed: 10/03/2023] Open
Abstract
The primary cilium is a single immotile microtubule-based organelle that protrudes into the extracellular space. Malformations and dysfunctions of the cilia have been associated with various forms of syndromic and non-syndromic diseases, termed ciliopathies. The primary cilium is therefore gaining attention due to its potential as a therapeutic target. In this review, we examine ciliary receptors, ciliogenesis, and ciliary trafficking as possible therapeutic targets. We first discuss the mechanisms of selective distribution, signal transduction, and physiological roles of ciliary receptors. Next, pathways that regulate ciliogenesis, specifically the Aurora A kinase, mammalian target of rapamycin, and ubiquitin-proteasome pathways are examined as therapeutic targets to regulate ciliogenesis. Then, in the photoreceptors, the mechanism of ciliary trafficking which takes place at the transition zone involving the ciliary membrane proteins is reviewed. Finally, some of the current therapeutic advancements highlighting the role of large animal models of photoreceptor ciliopathy are discussed.
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Affiliation(s)
- Masaki Saito
- Department of Molecular Physiology and Pathology, School of Pharma-Sciences, Teikyo University, Tokyo, Japan
| | - Wataru Otsu
- Department of Biomedical Research Laboratory, Gifu Pharmaceutical University, Gifu, Japan
| | - Keiko Miyadera
- Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Yuhei Nishimura
- Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
- Mie University Research Center for Cilia and Diseases, Tsu, Mie, Japan
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14
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Carotenuto P, Gradilone SA, Franco B. Cilia and Cancer: From Molecular Genetics to Therapeutic Strategies. Genes (Basel) 2023; 14:1428. [PMID: 37510333 PMCID: PMC10379587 DOI: 10.3390/genes14071428] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/07/2023] [Accepted: 07/09/2023] [Indexed: 07/30/2023] Open
Abstract
Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications.
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Affiliation(s)
- Pietro Carotenuto
- Medical Genetics, Department of Translational Medical Science, University of Naples “Federico II”, 80131 Naples, Italy
- TIGEM, Telethon Institute of Genetics and Medicine, 80078 Naples, Italy
| | - Sergio A. Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA;
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Brunella Franco
- Medical Genetics, Department of Translational Medical Science, University of Naples “Federico II”, 80131 Naples, Italy
- TIGEM, Telethon Institute of Genetics and Medicine, 80078 Naples, Italy
- School of Advanced Studies, Genomic and Experimental medicine Program (Scuola Superiore Meridionale), 80138 Naples, Italy
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15
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Li J, Qi Y, Li B, Liu Y, Yang K, Zhang Z, Zhu J, Du E. STIL/AURKA axis promotes cell proliferation by influencing primary cilia formation in bladder cancer. J Transl Med 2023; 21:281. [PMID: 37101292 PMCID: PMC10131372 DOI: 10.1186/s12967-023-04118-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 04/09/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND The primary cilia (PC) is a microtubule-based and nonmotile organelle which protrudes from the surface of almost all mammalian cells. At present, PC has been found to be a deficiency or loss in multiple cancers. Restoring PC could be a novel targeting therapy strategy. Our research showed that PC was reduced in human bladder cancer (BLCA) cells, and PC deficiency promotes cell proliferation. However, the concrete mechanisms remain unknown. SCL/TAL1 interrupting locus (STIL), a PC-related protein, was screened in our previous study and could influence the cell cycle by regulating PC in tumor cells. In this study, we aimed to elucidate the function of STIL for PC to explore the underlying mechanism of PC in BLCA. METHODS Public database analysis, western blot, and enzyme-linked immunosorbent assay (ELISA) were used to screen genes and explore gene expression alteration. Immunofluorescence and western blot were utilized to investigate PC. Wound healing assay, clone formation assay, and CCK-8 assay were used to explore cell migration, growth, and proliferation. The co-immunoprecipitation and western blot were employed to reveal the interaction of STIL and AURKA. RESULTS We found that high STIL expression is correlated with poor outcomes of BLCA patients. Further analysis revealed that STIL overexpression could inhibit PC formation, activate SHH signaling pathways, and promote cell proliferation. In contrast, STIL-knockdown could promote PC formation, inactivate SHH signaling, and inhibit cell proliferation. Furthermore, we found that the regulatory functions of STIL for PC depend on AURKA. STIL could influence proteasome activity and maintain AURKA stabilization. AURKA-knockdown could reverse PC deficiency caused by STIL overexpression for PC in BLCA cells. We observed that co-knockdown in STIL and AURKA significantly enhanced PC assembly. CONCLUSION In summary, our result provides a potential therapy target for BLCA based on the restoration of PC.
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Affiliation(s)
- Jingxian Li
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yuanjiong Qi
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Bo Li
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yan Liu
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Kuo Yang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Zhihong Zhang
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
| | - Jianqiang Zhu
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
| | - E Du
- Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
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16
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Mishra-Gorur K, Barak T, Kaulen LD, Henegariu O, Jin SC, Aguilera SM, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, Rai DK, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek AG, Bilguvar K, Lifton RP, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, Gunel M. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease. Proc Natl Acad Sci U S A 2023; 120:e2214997120. [PMID: 37043537 PMCID: PMC10120005 DOI: 10.1073/pnas.2214997120] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 02/27/2023] [Indexed: 04/13/2023] Open
Abstract
While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.
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Affiliation(s)
- Ketu Mishra-Gorur
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Tanyeri Barak
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Leon D. Kaulen
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | | | - Sheng Chih Jin
- Department of Genetics, Yale School of Medicine, New Haven, CT06510
| | | | - Ezgi Yalbir
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Gizem Goles
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Sayoko Nishimura
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | | | - Lydia Djenoune
- Cardiology Division, Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA02129
| | - Selin Altinok
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Devendra K. Rai
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Stephen Viviano
- Department of Pediatrics, Yale School of Medicine, New Haven, CT06510
| | - Andrew Prendergast
- Department of Internal Medicine, Section of Cardiology, Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT06510
| | - Cynthia Zerillo
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Kent Ozcan
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Burcin Baran
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Leman Sencar
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Nukte Goc
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | - Yanki Yarman
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
| | | | - Kaya Bilguvar
- Department of Genetics, Yale School of Medicine, New Haven, CT06510
| | - Richard P. Lifton
- Department of Genetics, Yale School of Medicine, New Haven, CT06510
- Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY10065
| | - Jennifer Moliterno
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
- Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT06510
| | - Angeliki Louvi
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
- Department of Neuroscience, Yale School of Medicine, New Haven, CT06510
| | - Shiaulou Yuan
- Cardiology Division, Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA02129
| | - Engin Deniz
- Department of Pediatrics, Yale School of Medicine, New Haven, CT06510
| | - Martina Brueckner
- Department of Pediatrics, Yale School of Medicine, New Haven, CT06510
| | - Murat Gunel
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT06510
- Department of Genetics, Yale School of Medicine, New Haven, CT06510
- Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT06510
- Department of Neuroscience, Yale School of Medicine, New Haven, CT06510
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17
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Pant K, Richard S, Peixoto E, Yin J, Seelig DM, Carotenuto P, Salati M, Franco B, Roberts LR, Gradilone SA. The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth. Cells 2023; 12:cells12050775. [PMID: 36899911 PMCID: PMC10001024 DOI: 10.3390/cells12050775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/20/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023] Open
Abstract
It is well established that Cholangiocarcioma (CCA) drug resistance plays a crucial role in the spread and survival of cancer cells. The major enzyme in the nicotinamide-adenine dinucleotide (NAD+)-mediated pathways, nicotinamide phosphoribosyltransferase (NAMPT), is essential for cancer cell survival and metastasis. Previous research has shown that the targeted NAMPT inhibitor FK866 reduces cancer cell viability and triggers cancer cell death; however, whether FK866 affects CCA cell survival has not been addressed before. We show herein that NAMPT is expressed in CCA cells, and FK866 suppresses the capacity of CCA cells to grow in a dose-dependent manner. Furthermore, by preventing NAMPT activity, FK866 significantly reduced the amount of NAD+ and adenosine 5'-triphosphate (ATP) in HuCCT1, KMCH, and EGI cells. The present study's findings further show that FK866 causes changes in mitochondrial metabolism in CCA cells. Additionally, FK866 enhances the anticancer effects of cisplatin in vitro. Taken together, the results of the current study suggest that the NAMPT/NAD+ pathway may be a possible therapeutic target for CCA, and FK866 may be a useful medication targeting CCA in combination with cisplatin.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Seth Richard
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Estanislao Peixoto
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Jun Yin
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55905, USA
| | - Davis M. Seelig
- Comparative Pathology Shared Resource, Masonic Cancer Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Pietro Carotenuto
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
- Medical Genetics, Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
| | - Massimiliano Salati
- Medical Oncology Unit, University Hospital of Modena, 41125 Modena, Italy
- Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 411250 Modena, Italy
| | - Brunella Franco
- Medical Genetics, Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy
- Genomics and Experimental Medicine Program, Scuola Superiore Meridionale, School for Advanced Studies, 80131 Naples, Italy
| | - Lewis R. Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Sergio A. Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Correspondence:
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18
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Senatore E, Iannucci R, Chiuso F, Delle Donne R, Rinaldi L, Feliciello A. Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation. Front Cell Dev Biol 2022; 10:833086. [PMID: 35646931 PMCID: PMC9130585 DOI: 10.3389/fcell.2022.833086] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/21/2022] [Indexed: 01/29/2023] Open
Abstract
Primary cilia are microtubule-based, non-motile sensory organelles present in most types of growth-arrested eukaryotic cells. They are transduction hubs that receive and transmit external signals to the cells in order to control growth, differentiation and development. Mutations of genes involved in the formation, maintenance or disassembly of ciliary structures cause a wide array of developmental genetic disorders, also known as ciliopathies. The primary cilium is formed during G1 in the cell cycle and disassembles at the G2/M transition. Following the completion of the cell division, the cilium reassembles in G1. This cycle is finely regulated at multiple levels. The ubiquitin-proteasome system (UPS) and the autophagy machinery, two main protein degradative systems in cells, play a fundamental role in cilium dynamics. Evidence indicate that UPS, autophagy and signaling pathways may act in synergy to control the ciliary homeostasis. However, the mechanisms involved and the links between these regulatory systems and cilium biogenesis, dynamics and signaling are not well defined yet. Here, we discuss the reciprocal regulation of signaling pathways and proteolytic machineries in the control of the assembly and disassembly of the primary cilium, and the impact of the derangement of these regulatory networks in human ciliopathies.
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19
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HDACs and the epigenetic plasticity of cancer cells: Target the complexity. Pharmacol Ther 2022; 238:108190. [PMID: 35430294 DOI: 10.1016/j.pharmthera.2022.108190] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022]
Abstract
Cancer cells must adapt to the hostile conditions of the microenvironment in terms of nutrition, space, and immune system attack. Mutations of DNA are the drivers of the tumorigenic process, but mutations must be able to hijack cellular functions to sustain the spread of mutant genomes. Transcriptional control is a key function in this context and is controlled by the rearrangement of the epigenome. Unlike genomic mutations, the epigenome of cancer cells can in principle be reversed. The discovery of the first epigenetic drugs triggered a contaminating enthusiasm. Unfortunately, the complexity of the epigenetic machinery has frustrated this enthusiasm. To develop efficient patient-oriented epigenetic therapies, we need to better understand the nature of this complexity. In this review, we will discuss recent advances in understanding the contribution of HDACs to the maintenance of the transformed state and the rational for their selective targeting.
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20
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Pant K, Richard S, Gradilone SA. Short-Chain Fatty Acid Butyrate Induces Cilia Formation and Potentiates the Effects of HDAC6 Inhibitors in Cholangiocarcinoma Cells. Front Cell Dev Biol 2022; 9:809382. [PMID: 35096835 PMCID: PMC8793355 DOI: 10.3389/fcell.2021.809382] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/09/2021] [Indexed: 12/19/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a deadly form of liver cancer with limited therapeutic approaches. The pathogenesis of CCA involves the loss of primary cilia in cholangiocytes, an important organelle that regulates several key cellular functions including the regulation of cell polarity, growth, and differentiation, by a mechanism involving increased expression of deacetylases like HDAC6 and SIRT1. Therefore, cilia restoration may represent an alternative and novel therapeutic approach against CCA. Butyrate is produced by bacterial fermentation of fibers in the intestine and has been shown to inhibit SIRT1, showing antitumor effects on various cancers. Herein, we investigated the role of butyrate on CCA cell proliferation, migration, and EMT and evaluated the synergistic effects with specific HDAC6 inhibition. When CCA cells, including HuCCT1 and KMCH, were treated with butyrate, the cilia formation and acetylated-tubulin levels were increased, while no significant effects were observed in normal human cholangiocytes. Butyrate treatment also depicted reduced cell proliferation in HuCCT1 and KMCH cells, but on the other hand, it affected cell growth of the normal cholangiocytes only at high concentrations. In HuCCT1 cells, spheroid formation and cell migration were also halted by butyrate treatment. Furthermore, we found that butyrate augmented the previously described effects of HDAC6 inhibitors on CCA cell proliferation and migration by reducing the expression of CD44, cyclin D1, PCNA, Zeb1, and Vimentin. In summary, butyrate targets cancer cell growth and migration and enhances the anti-cancer effects of HDAC6 inhibitors in CCA cells, suggesting that butyrate may have therapeutic effects in CCA and other ciliopathies.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, MN, United States
| | - Seth Richard
- The Hormel Institute, University of Minnesota, Austin, MN, United States
| | - Sergio A. Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN, United States
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
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21
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Pant K, Gradilone SA. Hepatobiliary Cancers: Progress in Diagnosis, Pathogenesis, and Treatment. Technol Cancer Res Treat 2022; 21:15330338221097203. [PMID: 35546130 PMCID: PMC9257325 DOI: 10.1177/15330338221097203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy result of hepatobiliary cancers is unsatisfactory due to these complicated variables, leaving significant space for improvement.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, 5635University of Minnesota, Austin, MN, USA
| | - Sergio A Gradilone
- The Hormel Institute, 5635University of Minnesota, Austin, MN, USA.,Masonic Cancer Center, 5635University of Minnesota, Minneapolis, MN, USA
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22
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Aurora A and AKT Kinase Signaling Associated with Primary Cilia. Cells 2021; 10:cells10123602. [PMID: 34944109 PMCID: PMC8699881 DOI: 10.3390/cells10123602] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Dysregulation of kinase signaling is associated with various pathological conditions, including cancer, inflammation, and autoimmunity; consequently, the kinases involved have become major therapeutic targets. While kinase signaling pathways play crucial roles in multiple cellular processes, the precise manner in which their dysregulation contributes to disease is dependent on the context; for example, the cell/tissue type or subcellular localization of the kinase or substrate. Thus, context-selective targeting of dysregulated kinases may serve to increase the therapeutic specificity while reducing off-target adverse effects. Primary cilia are antenna-like structures that extend from the plasma membrane and function by detecting extracellular cues and transducing signals into the cell. Cilia formation and signaling are dynamically regulated through context-dependent mechanisms; as such, dysregulation of primary cilia contributes to disease in a variety of ways. Here, we review the involvement of primary cilia-associated signaling through aurora A and AKT kinases with respect to cancer, obesity, and other ciliopathies.
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23
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Pant K, Peixoto E, Richard S, Biswas A, O'Sullivan MG, Giama N, Ha Y, Yin J, Carotenuto P, Salati M, Ren Y, Yang R, Franco B, Roberts LR, Gradilone SA. Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma. Hepatology 2021; 74:3235-3248. [PMID: 34322899 DOI: 10.1002/hep.32080] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 07/06/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Sirtuin 1 (SIRT1) is a complex NAD+ -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). APPROACH AND RESULTS A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. CONCLUSIONS In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.
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Affiliation(s)
- Kishor Pant
- The Hormel Institute, University of Minnesota, Austin, MN
| | | | - Seth Richard
- The Hormel Institute, University of Minnesota, Austin, MN
| | | | - M Gerard O'Sullivan
- Comparative Pathology Shared Resource, Masonic Cancer Center, University of Minnesota, St. Paul, MN
| | - Nasra Giama
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Yeonjung Ha
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Jun Yin
- Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN
| | - Pietro Carotenuto
- TIGEM, Telethon Institute of Genetics and Medicine, and Medical Genetics, Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Massimiliano Salati
- Medical Oncology Unit, Modena Cancer Centre, PhD Program Clinical and Experimental Medicine, University Hospital of Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Yanan Ren
- The Hormel Institute, University of Minnesota, Austin, MN
| | - Rendong Yang
- The Hormel Institute, University of Minnesota, Austin, MN
| | - Brunella Franco
- TIGEM, Telethon Institute of Genetics and Medicine, and Medical Genetics, Department of Translational Medical Science, Federico II University, Naples, Italy
| | - Lewis R Roberts
- Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Sergio A Gradilone
- The Hormel Institute, University of Minnesota, Austin, MN.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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24
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Insights into the Regulation of Ciliary Disassembly. Cells 2021; 10:cells10112977. [PMID: 34831200 PMCID: PMC8616418 DOI: 10.3390/cells10112977] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/15/2022] Open
Abstract
The primary cilium, an antenna-like structure that protrudes out from the cell surface, is present in most cell types. It is a microtubule-based organelle that serves as a mega-signaling center and is important for sensing biochemical and mechanical signals to carry out various cellular processes such as proliferation, migration, differentiation, and many others. At any given time, cilia length is determined by a dynamic balance of cilia assembly and disassembly processes. Abnormally short or long cilia can cause a plethora of human diseases commonly referred to as ciliopathies, including, but not limited to, skeletal malformations, obesity, autosomal dominant polycystic kidney disease, retinal degeneration, and bardet-biedl syndrome. While the process of cilia assembly is studied extensively, the process of cilia disassembly and its biological role(s) are less well understood. This review discusses current knowledge on ciliary disassembly and how different cellular processes and molecular signals converge to carry out this process. This information will help us understand how the process of ciliary disassembly is regulated, identify the key steps that need further investigation, and possibly design therapeutic targets for a subset of ciliopathies that are causally linked to defective ciliary disassembly.
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25
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Linder B, Klein C, Hoffmann ME, Bonn F, Dikic I, Kögel D. BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells. J Cell Biochem 2021; 123:77-90. [PMID: 34180073 DOI: 10.1002/jcb.30073] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/31/2021] [Accepted: 06/11/2021] [Indexed: 12/11/2022]
Abstract
By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.
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Affiliation(s)
- Benedikt Linder
- Department of Neurosurgery, Experimental Neurosurgery, University Hospital, Goethe University, Frankfurt am Main, Germany
| | - Caterina Klein
- Department of Neurosurgery, Experimental Neurosurgery, University Hospital, Goethe University, Frankfurt am Main, Germany.,Faculty of Biosciences, Goethe University, Frankfurt am Main, Germany
| | - Marina E Hoffmann
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
| | - Florian Bonn
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
| | - Ivan Dikic
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany.,Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt am Main, Germany
| | - Donat Kögel
- Department of Neurosurgery, Experimental Neurosurgery, University Hospital, Goethe University, Frankfurt am Main, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt, Frankfurt am Main, Germany.,German Cancer Research Center DKFZ, Heidelberg, Germany
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26
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Nita A, Abraham SP, Krejci P, Bosakova M. Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling. Cells 2021; 10:1445. [PMID: 34207779 PMCID: PMC8227969 DOI: 10.3390/cells10061445] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/27/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
A single primary cilium projects from most vertebrate cells to guide cell fate decisions. A growing list of signaling molecules is found to function through cilia and control ciliogenesis, including the fibroblast growth factor receptors (FGFR). Aberrant FGFR activity produces abnormal cilia with deregulated signaling, which contributes to pathogenesis of the FGFR-mediated genetic disorders. FGFR lesions are also found in cancer, raising a possibility of cilia involvement in the neoplastic transformation and tumor progression. Here, we focus on FGFR gene fusions, and discuss the possible mechanisms by which they function as oncogenic drivers. We show that a substantial portion of the FGFR fusion partners are proteins associated with the centrosome cycle, including organization of the mitotic spindle and ciliogenesis. The functions of centrosome proteins are often lost with the gene fusion, leading to haploinsufficiency that induces cilia loss and deregulated cell division. We speculate that this complements the ectopic FGFR activity and drives the FGFR fusion cancers.
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Affiliation(s)
- Alexandru Nita
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
| | - Sara P. Abraham
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
| | - Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
- Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
| | - Michaela Bosakova
- Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic; (A.N.); (S.P.A.); (P.K.)
- Institute of Animal Physiology and Genetics of the CAS, 60200 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic
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27
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Therapeutically actionable signaling node to rescue AURKA driven loss of primary cilia in VHL-deficient cells. Sci Rep 2021; 11:10461. [PMID: 34002003 PMCID: PMC8128866 DOI: 10.1038/s41598-021-89933-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 05/04/2021] [Indexed: 12/30/2022] Open
Abstract
Loss of primary cilia in cells deficient for the tumor suppressor von Hippel Lindau (VHL) arise from elevated Aurora Kinase A (AURKA) levels. VHL in its role as an E3 ubiquitin ligase targets AURKA for degradation and in the absence of VHL, high levels of AURKA result in destabilization of the primary cilium. We identified NVP-BEZ235, a dual PI3K/AKT and mTOR inhibitor, in an image-based high throughput screen, as a small molecule that restored primary cilia in VHL-deficient cells. We identified the ability of AKT to modulate AURKA expression at the transcript and protein level. Independent modulation of AKT and mTOR signaling decreased AURKA expression in cells confirming AURKA as a new signaling node downstream of the PI3K cascade. Corroborating these data, a genetic knockdown of AKT in cells deficient for VHL rescued the ability of these cells to ciliate. Finally, inhibition of AKT/mTOR using NVP-BEZ235 was efficacious in reducing tumor burden in a 786-0 xenograft model of renal cell carcinoma. These data highlight a previously unappreciated signaling node downstream of the AKT/mTOR pathway via AURKA that can be targeted in VHL-null cells to restore ciliogenesis.
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28
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Doornbos C, Roepman R. Moonlighting of mitotic regulators in cilium disassembly. Cell Mol Life Sci 2021; 78:4955-4972. [PMID: 33860332 PMCID: PMC8233288 DOI: 10.1007/s00018-021-03827-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/03/2021] [Accepted: 03/27/2021] [Indexed: 02/07/2023]
Abstract
Correct timing of cellular processes is essential during embryological development and to maintain the balance between healthy proliferation and tumour formation. Assembly and disassembly of the primary cilium, the cell’s sensory signalling organelle, are linked to cell cycle timing in the same manner as spindle pole assembly and chromosome segregation. Mitotic processes, ciliary assembly, and ciliary disassembly depend on the centrioles as microtubule-organizing centres (MTOC) to regulate polymerizing and depolymerizing microtubules. Subsequently, other functional protein modules are gathered to potentiate specific protein–protein interactions. In this review, we show that a significant subset of key mitotic regulator proteins is moonlighting at the cilium, among which PLK1, AURKA, CDC20, and their regulators. Although ciliary assembly defects are linked to a variety of ciliopathies, ciliary disassembly defects are more often linked to brain development and tumour formation. Acquiring a better understanding of the overlap in regulators of ciliary disassembly and mitosis is essential in finding therapeutic targets for the different diseases and types of tumours associated with these regulators.
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Affiliation(s)
- Cenna Doornbos
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ronald Roepman
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. .,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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29
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Juarez D, Fruman DA. Targeting the Mevalonate Pathway in Cancer. Trends Cancer 2021; 7:525-540. [PMID: 33358111 DOI: 10.1016/j.trecan.2020.11.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.
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Affiliation(s)
- Dennis Juarez
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
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30
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Ma CX, Ma XN, Li YD, Fu SB. The Role of Primary Cilia in Thyroid Cancer: From Basic Research to Clinical Applications. Front Endocrinol (Lausanne) 2021; 12:685228. [PMID: 34168619 PMCID: PMC8218906 DOI: 10.3389/fendo.2021.685228] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/24/2021] [Indexed: 12/07/2022] Open
Abstract
Primary cilia (PC) are microtubule-based organelles that are present on nearly all thyroid follicle cells and play an important role in physiological development and in maintaining the dynamic homeostasis of thyroid follicles. PC are generally lost in many thyroid cancers (TCs), and this loss has been linked to the malignant transformation of thyrocytes, which is regulated by PC-mediated signaling reciprocity between the stroma and cancer cells. Restoring PC on TC cells is a possible promising therapeutic strategy, and the therapeutic response and prognosis of TC are associated with the presence or absence of PC. This review mainly discusses the role of PC in the normal thyroid and TC as well as their potential clinical utility.
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Affiliation(s)
- Cheng-Xu Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, China
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xiao-Ni Ma
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, China
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Ying-Dong Li
- College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Song-Bo Fu
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, China
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
- *Correspondence: Song-Bo Fu,
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31
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Shiromizu T, Yuge M, Kasahara K, Yamakawa D, Matsui T, Bessho Y, Inagaki M, Nishimura Y. Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer. Int J Mol Sci 2020; 21:E5962. [PMID: 32825105 PMCID: PMC7504095 DOI: 10.3390/ijms21175962] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/16/2020] [Accepted: 08/17/2020] [Indexed: 12/17/2022] Open
Abstract
Cilia are antenna-like structures present in many vertebrate cells. These organelles detect extracellular cues, transduce signals into the cell, and play an essential role in ensuring correct cell proliferation, migration, and differentiation in a spatiotemporal manner. Not surprisingly, dysregulation of cilia can cause various diseases, including cancer and ciliopathies, which are complex disorders caused by mutations in genes regulating ciliary function. The structure and function of cilia are dynamically regulated through various mechanisms, among which E3 ubiquitin ligases and deubiquitinases play crucial roles. These enzymes regulate the degradation and stabilization of ciliary proteins through the ubiquitin-proteasome system. In this review, we briefly highlight the role of cilia in ciliopathy and cancer; describe the roles of E3 ubiquitin ligases and deubiquitinases in ciliogenesis, ciliopathy, and cancer; and highlight some of the E3 ubiquitin ligases and deubiquitinases that are potential therapeutic targets for these disorders.
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Affiliation(s)
- Takashi Shiromizu
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan; (T.S.); (M.Y.)
| | - Mizuki Yuge
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan; (T.S.); (M.Y.)
| | - Kousuke Kasahara
- Department of Physiology, Graduate School of Medicine, Mie University, Tsu, Mie 514-5807, Japan; (K.K.); (D.Y.); (M.I.)
| | - Daishi Yamakawa
- Department of Physiology, Graduate School of Medicine, Mie University, Tsu, Mie 514-5807, Japan; (K.K.); (D.Y.); (M.I.)
| | - Takaaki Matsui
- Gene Regulation Research, Division of Biological Sciences, Nara Institute of Science and Technology, Takayama, Nara 630-0192, Japan; (T.M.); (Y.B.)
| | - Yasumasa Bessho
- Gene Regulation Research, Division of Biological Sciences, Nara Institute of Science and Technology, Takayama, Nara 630-0192, Japan; (T.M.); (Y.B.)
| | - Masaki Inagaki
- Department of Physiology, Graduate School of Medicine, Mie University, Tsu, Mie 514-5807, Japan; (K.K.); (D.Y.); (M.I.)
| | - Yuhei Nishimura
- Department of Integrative Pharmacology, Graduate School of Medicine, Mie University, Tsu, Mie 514-8507, Japan; (T.S.); (M.Y.)
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32
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Guerra J, Chiodelli P, Tobia C, Gerri C, Presta M. Long-Pentraxin 3 Affects Primary Cilium in Zebrafish Embryo and Cancer Cells via the FGF System. Cancers (Basel) 2020; 12:cancers12071756. [PMID: 32630309 PMCID: PMC7409334 DOI: 10.3390/cancers12071756] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/29/2020] [Indexed: 11/16/2022] Open
Abstract
Primary cilium drives the left-right asymmetry process during embryonic development. Moreover, its dysregulation contributes to cancer progression by affecting various signaling pathways. The fibroblast growth factor (FGF)/FGF receptor (FGFR) system modulates primary cilium length and plays a pivotal role in embryogenesis and tumor growth. Here, we investigated the impact of the natural FGF trap long-pentraxin 3 (PTX3) on the determination of primary cilium extension in zebrafish embryo and cancer cells. The results demonstrate that down modulation of the PTX3 orthologue ptx3b causes the shortening of primary cilium in zebrafish embryo in a FGF-dependent manner, leading to defects in the left-right asymmetry determination. Conversely, PTX3 upregulation causes the elongation of primary cilium in FGF-dependent cancer cells. Previous observations have identified the PTX3-derived small molecule NSC12 as an orally available FGF trap with anticancer effects on FGF-dependent tumors. In keeping with the non-redundant role of the FGF/FGR system in primary cilium length determination, NSC12 induces the elongation of primary cilium in FGF-dependent tumor cells, thus acting as a ciliogenic anticancer molecule in vitro and in vivo. Together, these findings demonstrate the ability of the natural FGF trap PTX3 to exert a modulatory effect on primary cilium in embryonic development and cancer. Moreover, they set the basis for the design of novel ciliogenic drugs with potential implications for the therapy of FGF-dependent tumors.
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Affiliation(s)
- Jessica Guerra
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (J.G.); (P.C.); (C.T.); (C.G.)
| | - Paola Chiodelli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (J.G.); (P.C.); (C.T.); (C.G.)
| | - Chiara Tobia
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (J.G.); (P.C.); (C.T.); (C.G.)
| | - Claudia Gerri
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (J.G.); (P.C.); (C.T.); (C.G.)
- Francis Crick Institute, London NW1 1AT, UK
| | - Marco Presta
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (J.G.); (P.C.); (C.T.); (C.G.)
- Italian Consortium for Biotechnology (CIB), 25123 Brescia, Italy
- Correspondence:
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