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Ismail R, Habib HA, Anter AF, Amin A, Heeba GH. Modified citrus pectin ameliorates methotrexate-induced hepatic and pulmonary toxicity: role of Nrf2, galectin-3/TLR-4/NF-κB/TNF-α and TGF-β signaling pathways. Front Pharmacol 2025; 16:1528978. [PMID: 39917614 PMCID: PMC11798997 DOI: 10.3389/fphar.2025.1528978] [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: 11/15/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Introduction Methotrexate (MTX) is a frequently utilized anti-inflammatory and anticancer agent. Its potential liver and lung toxicity often limits its clinical effectiveness. We conducted this study to demonstrate the possible protective impacts of a natural galectin-3 (Gal-3) inhibitor, modified citrus pectin (MCP), against MTX-induced liver and lung toxicity and verify the potential signaling pathways of these suggested effects. In vitro, the cytotoxicity of MCP and its modulatory effect on MTX cytotoxic efficacy were assessed. Methods Four groups of rats were used: control, MTX (40 mg/kg, single intraperitoneal injection on day 9), MTX + MCP (200 mg/kg/day, orally, for 2 weeks), and MCP alone. MCF7, Nalm6, and JEG3 cell lines were used for the in vitro cytotoxicity assay. Results MCP counteracted liver and lung toxicity evidenced by ameliorating the markers of liver and lung functions. Moreover, MCP minimized oxidative stress elicited by MTX in lung and liver tissues, as indicated by reduced malondialdehyde levels, elevated levels of reduced glutathione, increased superoxide dismutase activity, and upregulated Nrf2 protein expression. In hepatic and pulmonary tissues, MCP downregulated the inflammatory signaling pathway, Gal-3/TLR-4/NF-κB/TNF-α. MCP pretreatment decreased TGF-β, collagen content, and cleaved caspase-3 levels. MCP enhanced the cytotoxicity of MTX in Nalm6 and JEG3 and did not interfere with its cytotoxicity in the MCF7 cell lines. Discussion MCP attenuated MTX-induced liver and lung toxicity through antioxidant, anti-fibrotic, anti-inflammatory, and anti-apoptotic influences, as demonstrated by the improved histopathological changes induced by MTX in pulmonary and hepatic tissues. Moreover, it increased MTX cytotoxicity in different human cell lines.
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Affiliation(s)
- Randa Ismail
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Heba A. Habib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Aliaa F. Anter
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
| | - Amr Amin
- College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Gehan H. Heeba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt
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Zhao Z, Wu J, Xu X, He Z, Wang X, Su J, Mayo KH, Sun L, Cui L, Zhou Y. Oligosaccharides from Stellaria dichotoma L. var. lanceolate bind to galectin-3 and ameliorate effects of colitis. Carbohydr Polym 2024; 345:122551. [PMID: 39227094 DOI: 10.1016/j.carbpol.2024.122551] [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: 05/23/2024] [Revised: 07/14/2024] [Accepted: 07/27/2024] [Indexed: 09/05/2024]
Abstract
Even though Stellaria dichotoma L. var. lanceolate (S. dichotoma) is a well-known medicinal plant in the family Caryophyllaceae, its oligosaccharides remain unexplored in terms of their potential as bioactive agents. Here, we isolated a mixture of oligosaccharides from S. dichotoma (Yield: 12 % w/w), that are primarily non-classical raffinose family oligosaccharides (RFOs). Nine major oligosaccharides were purified and identified from the mixture, including sucrose, raffinose, 1-planteose, lychnose, stellariose, along with four new non-classical RFOs. Two of the four new oligosaccharides are linear hexose pentamers with α-galactosyl extensions on their lychnose moieties, and the other two are branched hexose hexamers with α-galactosyl extensions on their stellariose groups. Their interactions with galectin-3 (Gal-3) revealed significant binding, with the terminal galactose providing enhanced affinity for the lectin. Notably, Gal-3 residues Arg144, His158, Asn160, Arg162, Asn174, Trp181, Glu184 and Arg186 coordinate with the lychnose. In vivo studies using the dextran sulfate sodium (DSS) mouse model for colitis demonstrated the ability of these carbohydrates in mitigating ulcerative colitis (UC). Overall, our study has provided structural information and potential applications of S. dichotoma oligosaccharides, also offers new approaches for the development of medicinal oligosaccharides.
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Affiliation(s)
- Zihan Zhao
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Jing Wu
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Xuejiao Xu
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Zhen He
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Xiang Wang
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Jiyong Su
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Kevin H Mayo
- Department of Biochemistry, Molecular Biology & Biophysics, 6-155 Jackson Hall, University of Minnesota, 321 Church Street, Minneapolis, MN 55455, USA
| | - Lin Sun
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China
| | - Liangnan Cui
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China.
| | - Yifa Zhou
- Engineering Research Center of Glycoconjugates, Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China.
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Lai C, Xu L, Dai S. The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials. Clin Transl Med 2024; 14:e1684. [PMID: 38783482 PMCID: PMC11116501 DOI: 10.1002/ctm2.1684] [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: 12/07/2023] [Revised: 04/15/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024] Open
Abstract
BACKGROUND Exportin-1 (XPO1), a crucial protein regulating nuclear-cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export-selective inhibitors has been increasing. Only KPT-330 (selinexor) has been successfully used for treating haematological malignancies, and KPT-8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export-selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours. METHODS We collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours. RESULTS In this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers. CONCLUSION XPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies. KEY POINTS Exportin-1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.
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Affiliation(s)
- Chuanxi Lai
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
| | - Lingna Xu
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
| | - Sheng Dai
- Department of Colorectal SurgerySir Run Run Shaw HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Key Laboratory of Biotherapy of Zhejiang ProvinceHangzhouChina
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Matoba Y, Zarrella DT, Pooladanda V, Azimi Mohammadabadi M, Kim E, Kumar S, Xu M, Qin X, Ray LJ, Devins KM, Kumar R, Kononenko A, Eisenhauer E, Veillard IE, Yamagami W, Hill SJ, Sarosiek KA, Yeku OO, Spriggs DR, Rueda BR. Targeting Galectin 3 illuminates its contributions to the pathology of uterine serous carcinoma. Br J Cancer 2024; 130:1463-1476. [PMID: 38438589 PMCID: PMC11058234 DOI: 10.1038/s41416-024-02621-x] [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: 09/23/2023] [Revised: 02/12/2024] [Accepted: 02/14/2024] [Indexed: 03/06/2024] Open
Abstract
BACKGROUND Uterine serous cancer (USC) comprises around 10% of all uterine cancers. However, USC accounts for approximately 40% of uterine cancer deaths, which is attributed to tumor aggressiveness and limited effective treatment. Galectin 3 (Gal3) has been implicated in promoting aggressive features in some malignancies. However, Gal3's role in promoting USC pathology is lacking. METHODS We explored the relationship between LGALS3 levels and prognosis in USC patients using TCGA database, and examined the association between Gal3 levels in primary USC tumors and clinical-pathological features. CRISPR/Cas9-mediated Gal3-knockout (KO) and GB1107, inhibitor of Gal3, were employed to evaluate Gal3's impact on cell function. RESULTS TCGA analysis revealed a worse prognosis for USC patients with high LGALS3. Patients with no-to-low Gal3 expression in primary tumors exhibited reduced clinical-pathological tumor progression. Gal3-KO and GB1107 reduced cell proliferation, stemness, adhesion, migration, and or invasion properties of USC lines. Furthermore, Gal3-positive conditioned media (CM) stimulated vascular tubal formation and branching and transition of fibroblast to cancer-associated fibroblast compared to Gal3-negative CM. Xenograft models emphasized the significance of Gal3 loss with fewer and smaller tumors compared to controls. Moreover, GB1107 impeded the growth of USC patient-derived organoids. CONCLUSION These findings suggest inhibiting Gal3 may benefit USC patients.
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Affiliation(s)
- Yusuke Matoba
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Dominique T Zarrella
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Venkatesh Pooladanda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Maryam Azimi Mohammadabadi
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Eugene Kim
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Shaan Kumar
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Mengyao Xu
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Xingping Qin
- Harvard T.H. Chan School of Public Health, Boston, MA, 02114, USA
| | - Lauren J Ray
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Kyle M Devins
- Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Raj Kumar
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Artem Kononenko
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Eric Eisenhauer
- Harvard Medical School, Boston, MA, 02115, USA
- Division Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Irva E Veillard
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Wataru Yamagami
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Sarah J Hill
- Harvard Medical School, Boston, MA, 02115, USA
- Department of Medical Oncology and Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | | | - Oladapo O Yeku
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - David R Spriggs
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Division of Hematology-Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Bo R Rueda
- Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
- Division Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, 02114, USA.
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Garrido G, Garrido-Suárez BB, Mieres-Arancibia M, Valdes-Gonzalez M, Ardiles-Rivera A. Modified pectin with anticancer activity in breast cancer: A systematic review. Int J Biol Macromol 2024; 254:127692. [PMID: 37898255 DOI: 10.1016/j.ijbiomac.2023.127692] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/21/2023] [Accepted: 10/25/2023] [Indexed: 10/30/2023]
Abstract
Breast cancer is the most commonly diagnosed cancer among women worldwide. The current pharmacological treatments for breast cancer have numerous adverse effects and are not always effective. Recently, the anticancer activity of modified pectins (MPs) against various types of cancers, including breast cancer, has been investigated. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model, including scientific articles from the last 22 years that measured the anticancer activity of MPs on breast cancer. The articles were searched in four databases with the terms: "modified pectin" and "breast cancer". Nine articles were included, five in vitro and four mixed (in vitro and in vivo). Different models and methods by which anticancer activity was measured were analyzed. All the studies reported positive results in both cell lines and in vivo murine models of breast cancer. The extracted data suggest a positive effect and provide mechanistic evidence of MPs in the treatment of breast cancer. However, as limited number of studies were included, further in vivo studies are required to obtain more conclusive preclinical evidence.
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Affiliation(s)
- Gabino Garrido
- Departamento de Ciencias Farmacéuticas, Universidad Católica del Norte, Angamos 0610, Antofagasta, Chile.
| | | | - Mario Mieres-Arancibia
- Departamento de Ciencias Farmacéuticas, Universidad Católica del Norte, Angamos 0610, Antofagasta, Chile
| | - Marisela Valdes-Gonzalez
- Departamento de Ciencias Farmacéuticas, Universidad Católica del Norte, Angamos 0610, Antofagasta, Chile
| | - Alejandro Ardiles-Rivera
- Departamento de Ciencias Básicas, Facultad de Ciencias, Universidad Santo Tomás, Antofagasta, Chile
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Woś J, Szymańska A, Lehman N, Chocholska S, Zarobkiewicz M, Pożarowski P, Bojarska-Junak A. Can Galectin-3 Be a Novel Biomarker in Chronic Lymphocytic Leukemia? Cells 2023; 13:30. [PMID: 38201234 PMCID: PMC10778116 DOI: 10.3390/cells13010030] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/05/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Galectin-3's (Gal-3) effect on the pathogenesis of chronic lymphocytic leukemia (CLL) has not yet been extensively studied. The present study aims to analyze the potential role of Gal-3 as a prognostic biomarker in CLL patients. The Gal-3 expression was evaluated in CLL cells with RT-qPCR and flow cytometry. Due to the unclear clinical significance of soluble Gal-3 in CLL, our goal was also to assess the prognostic value of Gal-3 plasma level. Because cell survival is significantly affected by the interaction between Gal-3 and proteins such as Bcl-2, the results of Gal-3 expression analysis were also compared with the expression of Bcl-2. The results were analyzed for known prognostic factors, clinical data, and endpoints such as time to first treatment and overall survival time. Our research confirmed that Gal-3 is detected in and on CLL cells. However, using Gal-3 as a potential biomarker in CLL is challenging due to the significant heterogeneity in its expression in CLL cells. Moreover, our results revealed that Gal-3 mRNA expression in leukemic B cells is associated with the expression of proliferation markers (Ki-67 and PCNA) as well as anti-apoptotic protein Bcl-2 and can play an important role in supporting CLL cells.
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Affiliation(s)
- Justyna Woś
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
| | - Agata Szymańska
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
| | - Natalia Lehman
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
| | - Sylwia Chocholska
- Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-080 Lublin, Poland;
| | - Michał Zarobkiewicz
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
| | - Piotr Pożarowski
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
| | - Agnieszka Bojarska-Junak
- Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland; (J.W.); (A.S.); (N.L.); (M.Z.); (P.P.)
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Picot-Allain MCN, Neergheen VS. Pectin a multifaceted biopolymer in the management of cancer: A review. Heliyon 2023; 9:e22236. [PMID: 38058641 PMCID: PMC10696011 DOI: 10.1016/j.heliyon.2023.e22236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/21/2023] [Accepted: 11/07/2023] [Indexed: 12/08/2023] Open
Abstract
This review article focuses on the multifaceted roles of pectin in cancer management, namely as an oncotherapeutic delivery vehicle and a pharmacological agent. Over the past decades, the potential of pectin as a novel therapeutical agent for the prevention and/or management of cancer has gained increasing interest. Pectin has been found to modulate different mechanisms involved in the onset and progression of carcinogenesis, such as galectin-3 inhibition, caspase-3-induced apoptosis, and autophagy. Elucidating the structure-activity relationship provides insight into the relationship between the structure of pectin and different mechanism/s. The bioactivity of pectin, with respect to its structure, was critically discussed to give a better insight of the relationship between the structure of the extracted pectin and the observed bioactive effects. The rhamnogalacturonan I part of the pectin chain was found to bind to galectin-3, associated with several cancer hallmarks. The anti-inflammatory and antioxidant potential of pectin were also described. The roles of pectin as a treatment enhancer and a drug delivery vehicle for oncotherapeutics were critically defined. The scientific findings presented in this paper are expected to highlight the potential and role of pectin recovered from various plant sources in preventing and managing cancer.
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Affiliation(s)
- Marie Carene Nancy Picot-Allain
- Biopharmaceutical Unit, Centre for Biomedical and Biomaterials Research, University of Mauritius, Réduit 80837, Mauritius
- Future Africa, University of Pretoria, South Africa
| | - Vidushi Shradha Neergheen
- Biopharmaceutical Unit, Centre for Biomedical and Biomaterials Research, University of Mauritius, Réduit 80837, Mauritius
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Tsai HP, Lin CJ, Lieu AS, Chen YT, Tseng TT, Kwan AL, Loh JK. Galectin-3 Mediates Tumor Progression in Astrocytoma by Regulating Glycogen Synthase Kinase-3β Activity. Curr Issues Mol Biol 2023; 45:3591-3602. [PMID: 37185758 PMCID: PMC10137203 DOI: 10.3390/cimb45040234] [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: 02/14/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 05/17/2023] Open
Abstract
Numerous studies have considered galectin-3 or Glycogen synthase kinase 3 beta (GSK3B) as a potential prognosis marker for various cancers. However, the correlation between the protein expression of galectin-3/GSK3B and the clinical parameters of astrocytoma has not been reported. This study aims to validate the correlation between the clinical outcomes and protein expression of galectin-3/GSK3B in astrocytoma. Immunohistochemistry staining was performed to detect galectin-3/GSK3B protein expression in patients with astrocytoma. The Chi-square test, Kaplan-Meier evaluation, and Cox regression analysis were used to determine the correlation between clinical parameters and galectin-3/GSK3B expression. Cell proliferation, invasion, and migration were compared between a non-siRNA group and a galectin-3/GSK3B siRNA group. Protein expression in galectin-3 or GSK3B siRNA-treated cells was evaluated using western blotting. Galectin-3 and GSK3B protein expression were significantly positively correlated with the World Health Organization (WHO) astrocytoma grade and overall survival time. Multivariate analysis revealed that WHO grade, galectin-3 expression, and GSK3B expression were independent prognostic factors for astrocytoma. Galectin-3 or GSK3B downregulation induced apoptosis and decreased cell numbers, migration, and invasion. siRNA-mediated gene silencing of galectin-3 resulted in the downregulation of Ki-67, cyclin D1, VEGF, GSK3B, p-GSK3B Ser9 (p-GSK3B S9), and β-catenin. In contrast, GSK3B knockdown only decreased Ki-67, VEGF, p-GSK3B S9, and β-catenin protein expression but did not affect cyclin D1 and galectin-3 protein expression. The siRNA results indicated that GSK3B is downstream of the galectin-3 gene. These data support that galectin-3 mediated tumor progression by upregulating GSK3B and β-catenin protein expression in glioblastoma. Therefore, galectin-3 and GSK3B are potential prognostic markers, and their genes may be considered to be anticancer targets for astrocytoma therapy.
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Affiliation(s)
- Hung-Pei Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Chien-Ju Lin
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ann-Shung Lieu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Yi-Ting Chen
- Department of Pathology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan
| | - Tzu-Ting Tseng
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Aij-Lie Kwan
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Neurosurgery, University of Virginia, Charlottesville, VA 22903, USA
| | - Joon-Khim Loh
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Bangarh R, Khatana C, Kaur S, Sharma A, Kaushal A, Siwal SS, Tuli HS, Dhama K, Thakur VK, Saini RV, Saini AK. Aberrant protein glycosylation: Implications on diagnosis and Immunotherapy. Biotechnol Adv 2023; 66:108149. [PMID: 37030554 DOI: 10.1016/j.biotechadv.2023.108149] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 03/10/2023] [Accepted: 04/04/2023] [Indexed: 04/10/2023]
Abstract
Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and cell-to-cell interaction. Alterations in the N-linked or O-linked glycosylation pattern of regulatory proteins like transcription factors or cellular receptors lead to many diseases, including cancer. These alterations give rise to micro- and macro-heterogeneity in tumor cells. Here, we review the role of O- and N-linked glycosylation and its regulatory function in autoimmunity and aberrant glycosylation in cancer. The change in cellular glycome could result from a change in the expression of glycosidases or glycosyltransferases like N-acetyl-glucosaminyl transferase V, FUT8, ST6Gal-I, DPAGT1, etc., impact the glycosylation of target proteins leading to transformation. Moreover, the mutations in glycogenes affect glycosylation patterns on immune cells leading to other related manifestations like pro- or anti-inflammatory effects. In recent years, understanding the glycome to cancer indicates that it can be utilized for both diagnosis/prognosis as well as immunotherapy. Studies involving mass spectrometry of proteome, site- and structure-specific glycoproteomics, or transcriptomics/genomics of patient samples and cancer models revealed the importance of glycosylation homeostasis in cancer biology. The development of emerging technologies, such as the lectin microarray, has facilitated research on the structure and function of glycans and glycosylation. Newly developed devices allow for high-throughput, high-speed, and precise research on aberrant glycosylation. This paper also discusses emerging technologies and clinical applications of glycosylation.
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Affiliation(s)
- Rashmi Bangarh
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Chainika Khatana
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Simranjeet Kaur
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Anchita Sharma
- Division of Biology, Indian Institute of Science Education and Research, Tirupati, Andhra Pradesh 517641, India
| | - Ankur Kaushal
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Samarjeet Singh Siwal
- Department of Chemistry, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Hardeep Singh Tuli
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly 243122, Uttar Pradesh, India
| | - Vijay Kumar Thakur
- Biorefining and Advanced Materials Research Center, Scotland's Rural College (SRUC), Kings Buildings, West Mains Road, Edinburgh EH9 3JG, United Kingdom; School of Engineering, University of Petroleum & Energy Studies (UPES), Dehradun 248007, Uttarakhand, India.
| | - Reena V Saini
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
| | - Adesh K Saini
- Department of Biotechnology, MMEC, Maharishi Markandeshwar (Deemed to Be University), Mullana-Ambala, Haryana 133207, India
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10
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Cellular Transcriptomics of Carboplatin Resistance in a Metastatic Canine Osteosarcoma Cell Line. Genes (Basel) 2023; 14:genes14030558. [PMID: 36980828 PMCID: PMC10048144 DOI: 10.3390/genes14030558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/18/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Osteosarcoma prognosis has remained unchanged for the past three decades. In both humans and canines, treatment is limited to excision, radiation, and chemotherapy. Chemoresistance is the primary cause of treatment failure, and the trajectory of tumor evolution while under selective pressure from treatment is thought to be the major contributing factor in both species. We sought to understand the nature of platinum-based chemotherapy resistance by investigating cells that were subjected to repeated treatment and recovery cycles with increased carboplatin concentrations. Three HMPOS-derived cell lines, two resistant and one naïve, underwent single-cell RNA sequencing to examine transcriptomic perturbation and identify pathways leading to resistance and phenotypic changes. We identified the mechanisms of acquired chemoresistance and inferred the induced cellular trajectory that evolved with repeated exposure. The gene expression patterns indicated that acquired chemoresistance was strongly associated with a process similar to epithelial–mesenchymal transition (EMT), a phenomenon associated with the acquisition of migratory and invasive properties associated with metastatic disease. We conclude that the observed trajectory of tumor adaptability is directly correlated with chemoresistance and the phase of the EMT-like phenotype is directly affected by the level of chemoresistance. We infer that the EMT-like phenotype is a critical component of tumor evolution under treatment pressure and is vital to understanding the mechanisms of chemoresistance and to improving osteosarcoma prognosis.
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11
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Skubleny D, Lin A, Garg S, McLean R, McCall M, Ghosh S, Spratlin JL, Schiller D, Rayat G. Increased CD4/CD8 Lymphocyte ratio predicts favourable neoadjuvant treatment response in gastric cancer: A prospective pilot study. World J Gastrointest Oncol 2023; 15:303-317. [PMID: 36908322 PMCID: PMC9994053 DOI: 10.4251/wjgo.v15.i2.303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/25/2022] [Accepted: 01/12/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Despite optimal neoadjuvant chemotherapy only 40% of gastric cancer tumours achieve complete or partial treatment response. In the absence of treatment response, neoadjuvant chemotherapy in gastric cancer contributes to adverse events without additional survival benefit compared to adjuvant treatment or surgery alone. Additional strategies and methods are required to optimize the allocation of existing treatment regimens such as FLOT chemotherapy (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel). Predictive biomarkers detected using immunohistochemistry (IHC) methods may provide useful data regarding treatment response.
AIM To investigate the utility of CD4, CD8, Galectin-3 and E-cadherin in predicting neoadjuvant FLOT chemotherapy tumour response in gastric adenocarcinoma.
METHODS Forty-three adult patients with gastric adenocarcinoma, of which 18 underwent neoadjuvant chemotherapy, were included in a prospective clinical cohort. Endoscopic biopsies were obtained from gastric cancer and normal adjacent gastric mucosa. Differences in expression of Galectin-3, E-cadherin, CD4+ and CD8+ molecules between tumours with and without treatment response to neoadjuvant chemotherapy were assessed with IHC. Treatment response was graded by clinical pathologists using the Tumour Regression Score according to the College of American Pathologists criteria. Treatment response was defined as complete or near complete tumour response, whereas partial or poor/no response was defined as incomplete. Digital IHC images were annotated and quantitatively assessed using QuPath 0.3.1. Biomarker expression between responsive and incomplete response tumours was assessed using a two-sided Wilcoxon test. Biomarker expression was also compared between normal and cancer tissue and between 15 paired tumour samples before and after chemotherapy. We performed a preliminary multivariate analysis and power analysis to guide future study. Statistical analyses were completed using R 4.1.2.
RESULTS The ratio between CD4+ and CD8+ lymphocytes was significantly greater in treatment responsive tumours (Wilcoxon, P = 0.03). In univariate models, CD4+/CD8+ ratio was the only biomarker that significantly predicted favourable treatment response (Accuracy 86%, P < 0.001). Using a glmnet multivariate model, high CD4+/CD8+ ratio and low Galectin-3 expression were the most influential variables in predicting a favourable treatment response. Analyses of paired samples found that FLOT chemotherapy also results in increased expression of CD4+ and CD8+ tumour infiltrating lymphocytes (Paired Wilcoxon, P = 0.002 and P = 0.008, respectively). Our power analysis suggests future study requires at least 35 patients in each treatment response group for CD8 and Galectin-3 molecules, whereas 80 patients in each treatment response group are required to assess CD4 and E-cadherin biomarkers.
CONCLUSION We demonstrate that an elevated CD4+/CD8+ Ratio is a promising IHC-based biomarker to predict favourable treatment response to FLOT neoadjuvant chemotherapy in locally advanced gastric cancer.
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Affiliation(s)
- Daniel Skubleny
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, AB, Canada
| | - Andrea Lin
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Saurabh Garg
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Ross McLean
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Michael McCall
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Sunita Ghosh
- Department of Oncology, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Jennifer L Spratlin
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton T5G 1Z2, AB, Canada
| | - Daniel Schiller
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
| | - Gina Rayat
- Department of Surgery, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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12
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Basaran MM, Arslan H, Candar T. Serum galectin‑3 and α‑1‑acid glycoprotein levels in diagnosis and prognosis of idiopathic sudden sensorineural hearing loss. Exp Ther Med 2023; 25:122. [PMID: 36815966 PMCID: PMC9934003 DOI: 10.3892/etm.2023.11821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 11/04/2022] [Indexed: 02/05/2023] Open
Abstract
Idiopathic sudden sensorineural hearing loss (ISSNHL) is an otological emergency in which etiopathogenesis remains unclear. A number of disorders is considered as the cause; therefore, different treatment modalities are used without certainty of a cure. The present study aimed to analyse the potential correlation between serum α-1-acid glycoprotein (AGP) and galectin-3 levels with ISSNHL, and to investigate markers for guidance of treatment. A total of 55 patients with ISSNHL [29 (52.7%) female, 26 male, mean age, 46.76±17.68 years] and 47 healthy volunteers [25 (53.2%) female, 21 male, mean age, 43.95±12.96 years) were included in the study. The complete blood count, erythrocyte sedimentation rate, C-reactive protein, serum galectin-3 and AGP levels were evaluated. The audiological investigation included pure tone average and speech discrimination scores were also recorded before and after corticosteroid treatment. Serum AGP levels in the study group vs. the control group were 64.08±25.10 and 67.01±21.59 mg/dl (P=0.53), respectively. Galectin-3 levels were 16.80±4.55 in the study group and 15.15±3.74 ng/ml in the control group (P=0.05). Serum galectin-3 levels were significantly correlated with unresponsiveness to treatment (P<0.001). Galectin-3 is an important biomarker for patients with ISSNHL. Patients with high serum galectin-3 levels may be unresponsive to standard therapy.
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Affiliation(s)
- Mustafa Mert Basaran
- Department of Otorhinolaryngology, Kafkas University, Kars, Merkez 36100, Turkey
| | - Hande Arslan
- Department of Otorhinolaryngology, Samsun Education and Research Hospital, Samsun 55090, Turkey,Correspondence to: Dr Hande Arslan, Department of Otorhinolaryngology, Samsun Education and Research Hospital, Kavacik Baris Bulvari, Ilkadim, Samsun 55090, Turkey
| | - Tuba Candar
- Department of Biochemistry, Ufuk University, Ankara 06530, Turkey
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13
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Wang J, Gao N, Wang X, Yu W, Li A. Prognostic Factors in Acute Myeloid Leukemia with t(8;21)/ AML1-ETO: Strategies to Define High-Risk Patients. Indian J Hematol Blood Transfus 2022; 38:631-637. [PMID: 36258727 PMCID: PMC9569252 DOI: 10.1007/s12288-021-01507-9] [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: 07/24/2021] [Accepted: 11/25/2021] [Indexed: 10/19/2022] Open
Abstract
Acute myeloid leukemia (AML) with t(8;21)/AML1-ETO is considered to have favorable prognosis. However, outcome is not universally satisfactory. The aim of this study was to search for potential prognostic risk factors which can help individualized treatment in t(8;21) AML patients. All available clinical and laboratory indicators were analyzed retrospectively in 103 t (8;21) AML patients. All patients were followed up for median of 30 months (range 0.3-73 months). CD56 and IDH1 were found to be closely related to high recurrence (p = 0.002; p = 0.001) and incidence of cumulative recurrence (p = 0.001; p < 0.0001). C-KIT was associated with a high cumulative incidence of non-relapse mortality (p < 0.0001). Elevated galectin-3 (gal-3) had a significantly adverse effect on overall survival (OS) and disease-free survival (DFS) of patients receiving standard-dose cytarabine-based consolidation chemotherapy. In multivariable analysis, gal-3 (p = 0.01), CD56 (p = 0.002), IDH1 (p = 0.007) and C-KIT (p = 0.041) were the independent unfavorable factors for OS. CD56 (p = 0.019), IDH1 (p = 0.001) and consolidation chemotherapy regimen (p = 0.041) were the independent risk factors in terms of DFS. A scoring system incorporating gal-3, CD56, IDH1 and C-KIT proved to be helpful for predicting OS in t (8;21) AML patients. Our results revealed that those carrying four factors mentioned above should be considered to be high-risk patients.
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Affiliation(s)
- Jianyong Wang
- Department of Pediatric Hematology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000 Shandong China
| | - Na Gao
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, 256600 Shandong China
| | - Xuexia Wang
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, 256600 Shandong China
| | - Wenzheng Yu
- Department of Hematology, Binzhou Medical University Hospital, Binzhou, 256600 Shandong China
| | - Aimin Li
- Department of Pediatric Hematology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000 Shandong China
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14
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Herrador-Cañete G, Zalacain M, Labiano S, Laspidea V, Puigdelloses M, Marrodan L, Garcia-Moure M, Gonzalez-Huarriz M, Marco-Sanz J, Ausejo-Mauleon I, de la Nava D, Hernández-Osuna R, Martínez-García J, Silva-Pilipich N, Gurucega E, Patiño-García A, Hernández-Alcoceba R, Smerdou C, Alonso MM. Galectin-3 inhibition boosts the therapeutic efficacy of Semliki Forest virus in pediatric osteosarcoma. Mol Ther Oncolytics 2022; 26:246-264. [PMID: 35949950 PMCID: PMC9345771 DOI: 10.1016/j.omto.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/07/2022] [Indexed: 12/04/2022] Open
Abstract
The outcomes of metastatic and nonresponder pediatric osteosarcoma patients are very poor and have not improved in the last 30 years. These tumors harbor a highly immunosuppressive environment, making existing immunotherapies ineffective. Here, we evaluated the use of Semliki Forest virus (SFV) vectors expressing galectin-3 (Gal3) inhibitors as therapeutic tools, since both the inhibition of Gal3, which is involved in immunosuppression and metastasis, and virotherapy based on SFV have been demonstrated to reduce tumor progression in different tumor models. In vitro, inhibitors based on the Gal3 amino-terminal domain alone (Gal3-N) or fused to a Gal3 peptide inhibitor (Gal3-N-C12) were able to block the binding of Gal3 to the surface of activated T cells. In vivo, SFV expressing Gal3-N-C12 induced strong antitumor responses in orthotopic K7M2 and MOS-J osteosarcoma tumors, leading to complete regressions in 47% and 30% of mice, respectively. Pulmonary metastases were also reduced in K7M2 tumor-bearing mice after treatment with SFV-Gal3-N-C12. Both the antitumor and antimetastatic responses were dependent on modulation of the immune system, primarily including an increase in tumor-infiltrating lymphocytes and a reduction in the immunosuppressive environment inside tumors. Our results demonstrated that SFV-Gal3-N-C12 could constitute a potential therapeutic agent for osteosarcoma patients expressing Gal3.
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Affiliation(s)
- Guillermo Herrador-Cañete
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Gene Therapy and Regulation of Gene Expression Program, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Marta Zalacain
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Sara Labiano
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Virginia Laspidea
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Montserrat Puigdelloses
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Lucía Marrodan
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Marc Garcia-Moure
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Marisol Gonzalez-Huarriz
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Javier Marco-Sanz
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Iker Ausejo-Mauleon
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Daniel de la Nava
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Reyes Hernández-Osuna
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Javier Martínez-García
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Gene Therapy and Regulation of Gene Expression Program, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Noelia Silva-Pilipich
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Gene Therapy and Regulation of Gene Expression Program, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Elisabeth Gurucega
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Bioinformatics Platform, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Ana Patiño-García
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
| | - Rubén Hernández-Alcoceba
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Gene Therapy and Regulation of Gene Expression Program, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Cristian Smerdou
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Gene Therapy and Regulation of Gene Expression Program, Cima Universidad de Navarra, Pamplona 31008, Spain
| | - Marta M Alonso
- Health Research Institute of Navarra (IdiSNA), Pamplona 31008, Spain.,Solid Tumor Program, Cima Universidad de Navarra, Pamplona 31008, Spain.,Department of Pediatrics, Clínica Universidad de Navarra, Pamplona 31008, Spain
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15
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Jahan S, Mukherjee S, Ali S, Bhardwaj U, Choudhary RK, Balakrishnan S, Naseem A, Mir SA, Banawas S, Alaidarous M, Alyenbaawi H, Iqbal D, Siddiqui AJ. Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects. Cells 2022; 11:490. [PMID: 35159299 PMCID: PMC8833976 DOI: 10.3390/cells11030490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.
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Affiliation(s)
- Sadaf Jahan
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shouvik Mukherjee
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Shaheen Ali
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Urvashi Bhardwaj
- Department of Biotechnology, School of Chemical and Life Sciences, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ranjay Kumar Choudhary
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Santhanaraj Balakrishnan
- Medical Equipment Technology, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Asma Naseem
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Shabir Ahmad Mir
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Saeed Banawas
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
- Department of Biomedical Sciences, Oregon State University, Corvallis, OR 97331, USA
| | - Mohammed Alaidarous
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Hadeel Alyenbaawi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Danish Iqbal
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al-Majmaah 11952, Saudi Arabia
| | - Arif Jamal Siddiqui
- Department of Biology, College of Science, University of Hail, Hail 81451, Saudi Arabia
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16
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Ornelas AC, Ferguson S, DePlaza M, Adekunle T, Basha R. Anti-Cancer Pectins and Their Role in Colorectal Cancer Treatment. ONCO THERAPEUTICS 2022; 9:43-55. [PMID: 37309487 PMCID: PMC10259824 DOI: 10.1615/oncotherap.v9.i2.50] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
A class of plant polysaccharides, pectin is known to display several medicinal properties including in cancer. There is some evidence that pectin from some fruits can reduce the severity of colorectal cancer (CRC) due to its antiproliferative, anti-inflammatory, antimetastatic and pro-apoptotic properties. Pectin fermentation in the colon induces antiproliferative activity via butyrate. Research also showed that pectin acts as a potent inducer of programmed cell death and cell-cycle arrest, thereby selectively targeting cancer cells. Pectin can limit oxidative stress to maintain cellular homeostasis while increasing reactive oxygen species damage to activate cancer cell death. Pectin regulates various signaling cascades, e.g., signal transduction and transcriptional activator and mitogen-activated protein kinase signaling, that contribute to its anticancer activity. By curbing inflammation-activated signaling and bolstering immune-protective mechanisms pectin can eradicate CRC. Due to its chemical structure, pectin can also inhibit galectin-3 and suppress tumor growth and metastasis. Prior reports also suggested that pectin is beneficial to use alongside the CRC standard care. Pectin can increase sensitivity to conventional CRC drugs, alleviate unwanted side effects and reduce drug resistance. Although some preclinical studies are promising, early clinical trials are showing some evidence for pectin's efficacy in tumor growth inhibition and preventing metastasis in some cancers; however, the clinical use of pectin in CRC therapy is not yet well established. Further studies are needed to confirm the efficacy of pectin treatment as a valid clinical therapy for CRC in humans.
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Affiliation(s)
| | - Sam Ferguson
- Department of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA
| | - Maya DePlaza
- Texas College of Osteopathic Medicine, The University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA
| | - Tkai Adekunle
- Department of Biology, Savannah State University, Savannah, GA 31404, USA
| | - Riyaz Basha
- Department of Pediatrics and Women’s Health, Texas College of Osteopathic Medicine, The University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA
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17
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Donadio JLS, Prado SBRD, Rogero MM, Fabi JP. Effects of pectins on colorectal cancer: targeting hallmarks as a support for future clinical trials. Food Funct 2022; 13:11438-11454. [DOI: 10.1039/d2fo01995g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The intake of dietary fibers has been associated with a reduction in the risk of colorectal cancer.
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Affiliation(s)
- Janaina L. S. Donadio
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
- Food Research Center (FoRC), CEPID-FAPESP (Research, Innovation and Dissemination Centers, São Paulo Research Foundation), São Paulo, Brazil
| | | | - Marcelo M. Rogero
- Food Research Center (FoRC), CEPID-FAPESP (Research, Innovation and Dissemination Centers, São Paulo Research Foundation), São Paulo, Brazil
- Department of Nutrition, School of Public Health University of São Paulo, Sao Paulo, Brazil
| | - João Paulo Fabi
- Department of Food Science and Experimental Nutrition, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
- Food Research Center (FoRC), CEPID-FAPESP (Research, Innovation and Dissemination Centers, São Paulo Research Foundation), São Paulo, Brazil
- Food and Nutrition Research Center (NAPAN), University of São Paulo, São Paulo, Brazil
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18
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Patel V, Szász I, Koroknai V, Kiss T, Balázs M. Molecular Alterations Associated with Acquired Drug Resistance during Combined Treatment with Encorafenib and Binimetinib in Melanoma Cell Lines. Cancers (Basel) 2021; 13:cancers13236058. [PMID: 34885166 PMCID: PMC8656772 DOI: 10.3390/cancers13236058] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/21/2022] Open
Abstract
Combination treatment using BRAF/MEK inhibitors is a promising therapy for patients with advanced BRAFV600E/K mutant melanoma. However, acquired resistance largely limits the clinical efficacy of this drug combination. Identifying resistance mechanisms is essential to reach long-term, durable responses. During this study, we developed six melanoma cell lines with acquired resistance for BRAFi/MEKi treatment and defined the molecular alterations associated with drug resistance. We observed that the invasion of three resistant cell lines increased significantly compared to the sensitive cells. RNA-sequencing analysis revealed differentially expressed genes that were functionally linked to a variety of biological functions including epithelial-mesenchymal transition, the ROS pathway, and KRAS-signalling. Using proteome profiler array, several differentially expressed proteins were detected, which clustered into a unique pattern. Galectin showed increased expression in four resistant cell lines, being the highest in the WM1617E+BRes cells. We also observed that the resistant cells behaved differently after the withdrawal of the inhibitors, five were not drug addicted at all and did not exhibit significantly increased lethality; however, the viability of one resistant cell line (WM1617E+BRes) decreased significantly. We have selected three resistant cell lines to investigate the protein expression changes after drug withdrawal. The expression patterns of CapG, Enolase 2, and osteopontin were similar in the resistant cells after ten days of "drug holiday", but the Snail protein was only expressed in the WM1617E+BRes cells, which showed a drug-dependent phenotype, and this might be associated with drug addiction. Our results highlight that melanoma cells use several types of resistance mechanisms involving the altered expression of different proteins to bypass drug treatment.
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Affiliation(s)
- Vikas Patel
- Doctoral School of Health Sciences, University of Debrecen, 4032 Debrecen, Hungary;
| | - István Szász
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Viktória Koroknai
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Tímea Kiss
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Margit Balázs
- MTA-DE Public Health Research Group, University of Debrecen, 4032 Debrecen, Hungary; (I.S.); (V.K.)
- Department of Public Health and Epidemiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
- Correspondence:
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Yin P, Cui S, Liao X, Yao X. Galectin‑3 blockade suppresses the growth of cetuximab‑resistant human oral squamous cell carcinoma. Mol Med Rep 2021; 24:685. [PMID: 34328195 PMCID: PMC8365594 DOI: 10.3892/mmr.2021.12325] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/28/2021] [Indexed: 11/09/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with OSCC due to unknown mechanisms. Galectin‑3 (Gal‑3) is a β‑galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal‑3 in cetuximab‑resistant (cet‑R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal‑3 inhibitor was used to treat cet‑R tumors, and the tumor volume was monitored. The expression of Gal‑3, phosphorylated (p)‑ERK1/2 and p‑Akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal‑3 inhibitor on HSC3 tumor xenografts was also investigated. HSC3 cells were cultured in vitro to investigate the regulatory effects of Gal‑3 on ERK1/2 and Akt via western blotting. In addition, the effects of the Gal‑3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSC3 cells were investigated by performing Cell Counting Kit‑8, colony formation, Transwell and apoptosis assays, respectively. In cet‑R OSCC tumors, increased expression of Gal‑3, p‑ERK1/2 and p‑Akt was observed. Further research demonstrated that Gal‑3 regulated the expression of both ERK1/2 and Akt in HSC3 cells by promoting phosphorylation. Moreover, the Gal‑3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet‑R HSC3 cells. In addition, the Gal‑3 inhibitor suppressed the growth of cet‑R tumors. Collectively, the results indicated that the Gal‑3 inhibitor and cetuximab displayed a synergistic inhibitory effect on OSCC tumors. In summary, the present study demonstrated that Gal‑3 may serve an important role in cet‑R OSCC. The combination of cetuximab and the Gal‑3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.
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Affiliation(s)
- Peng Yin
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing 110112, P.R. China
| | - Shuanlong Cui
- Department of Stomatology, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiangling Liao
- Department of Stomatology, Beijing Luhe Hospital, Capital Medical University, Beijing 110112, P.R. China
| | - Xiaoguang Yao
- Department of Surgery, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050011, P.R. China
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Kremsreiter SM, Kroell ASH, Weinberger K, Boehm H. Glycan-Lectin Interactions in Cancer and Viral Infections and How to Disrupt Them. Int J Mol Sci 2021; 22:10577. [PMID: 34638920 PMCID: PMC8508825 DOI: 10.3390/ijms221910577] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 02/07/2023] Open
Abstract
Glycan-lectin interactions play an essential role in different cellular processes. One of their main functions is involvement in the immune response to pathogens or inflammation. However, cancer cells and viruses have adapted to avail themselves of these interactions. By displaying specific glycosylation structures, they are able to bind to lectins, thus promoting pathogenesis. While glycan-lectin interactions promote tumor progression, metastasis, and/or chemoresistance in cancer, in viral infections they are important for viral entry, release, and/or immune escape. For several years now, a growing number of investigations have been devoted to clarifying the role of glycan-lectin interactions in cancer and viral infections. Various overviews have already summarized and highlighted their findings. In this review, we consider the interactions of the lectins MGL, DC-SIGN, selectins, and galectins in both cancer and viral infections together. A possible transfer of ways to target and disrupt them might lead to new therapeutic approaches in different pathological backgrounds.
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Affiliation(s)
- Stefanie Maria Kremsreiter
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Ann-Sophie Helene Kroell
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Katharina Weinberger
- Institute for Pharmacy and Molecular Biotechnology (IPMB), Ruprecht Karls University Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; (S.M.K.); (A.-S.H.K.); (K.W.)
| | - Heike Boehm
- Max-Planck-Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany
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Indispensable role of Galectin-3 in promoting quiescence of hematopoietic stem cells. Nat Commun 2021; 12:2118. [PMID: 33837181 PMCID: PMC8035175 DOI: 10.1038/s41467-021-22346-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 03/14/2021] [Indexed: 12/20/2022] Open
Abstract
Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence. The cellular mechanism coordinating the balance between HSC quiescence and differentiation is not fully understood. Here, we report that galactose-binding lectin-3 (galectin-3; Gal-3) is upregulated by Tie2 or Mpl activation to maintain quiescence. Conditional overexpression of Gal-3 in mouse HSCs under the transcriptional control of Tie2 or Vav1 promoters (Gal-3 Tg) causes cell cycle retardation via induction of p21. Conversely, the cell cycle of long-term repopulating HSCs (LT-HSCs) in Gal-3-deficient (Gal-3-/-) mice is accelerated, resulting in their exhaustion. Mechanistically, Gal-3 regulates p21 transcription by forming a complex with Sp1, thus blocking cell cycle entry. These results demonstrate that Gal-3 is a negative regulator of cell-cycling in HSCs and plays a crucial role in adult hematopoiesis to prevent HSC exhaustion. Long term haematopoitic stem cells (LT-HSCs) are in a quiescent state during homeostasis, which is critical for their maintenance. Here, the authors show that Gal-3 expression in LT-HSCs is induced in response to Tie2 and Mpl and is both necessary and sufficient for LT-HSC quiescence through regulation of p21.
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Kusuhara S, Igawa S, Ichinoe M, Nagashio R, Kuchitsu Y, Hiyoshi Y, Shiomi K, Murakumo Y, Saegusa M, Satoh Y, Sato Y, Naoki K. Prognostic significance of galectin-3 expression in patients with resected NSCLC treated with platinum-based adjuvant chemotherapy. Thorac Cancer 2021; 12:1570-1578. [PMID: 33793071 PMCID: PMC8107024 DOI: 10.1111/1759-7714.13945] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/05/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Galectin-3 (GAL3), a protein encoded by the LGALS3 gene, plays diverse roles in cancer initiation, progression, and drug resistance. Accordingly, high GAL3 expression in tumor cells is associated with poor prognosis in non-small cell lung cancer (NSCLC). However, the prognostic impact of GAL3 expression on patients with resected NSCLC receiving platinum-based adjuvant chemotherapy (AC) remains unclear. This study aimed to determine the prognostic significance of GAL3 expression in NSCLC patients receiving platinum-based AC. METHODS The study included 111 patients with completely resected stages II and IIIA NSCLC who were receiving platinum-based AC. GAL3 expression in cancer cells was evaluated immunohistochemically according to H-score ("histo score), with a score of ≥170 considered as high expression. The correlation of GAL3 expression with clinicopathological characteristics and survival was subsequently evaluated. RESULTS In survival analysis, GAL3 expression was significantly associated with recurrence-free survival (RFS) and overall survival (OS). In multivariate analysis, GAL3 expression was an independent predictive factor of RFS rather than OS. CONCLUSIONS GAL3 expression is a reliable biomarker to predict the prognosis of completely resected NSCLC patients receiving platinum-based AC.
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Affiliation(s)
- Seiichiro Kusuhara
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Satoshi Igawa
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Masaaki Ichinoe
- Department of Pathology, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Ryo Nagashio
- Department of Pathology, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Yuki Kuchitsu
- Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan
| | - Yasuhiro Hiyoshi
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Kazu Shiomi
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Yoshiki Murakumo
- Department of Pathology, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Makoto Saegusa
- Department of Pathology, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Yukitoshi Satoh
- Department of Thoracic and Cardiovascular Surgery, School of Medicine, Kitasato University, Sagamihara, Japan
| | - Yuichi Sato
- Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan
| | - Katsuhiko Naoki
- Department of Respiratory Medicine, School of Medicine, Kitasato University, Sagamihara, Japan
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Pedrosa LDF, Lopes RG, Fabi JP. The acid and neutral fractions of pectins isolated from ripe and overripe papayas differentially affect galectin-3 inhibition and colon cancer cell growth. Int J Biol Macromol 2020; 164:2681-2690. [DOI: 10.1016/j.ijbiomac.2020.08.135] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/03/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022]
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Navarro P, Martínez-Bosch N, Blidner AG, Rabinovich GA. Impact of Galectins in Resistance to Anticancer Therapies. Clin Cancer Res 2020; 26:6086-6101. [DOI: 10.1158/1078-0432.ccr-18-3870] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/27/2020] [Accepted: 07/22/2020] [Indexed: 11/16/2022]
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Chain MDO, Paiva CADM, Maciel IO, Neto AN, Castro VFD, Oliveira CPD, Mendonça BDS, Nestal de Moraes G, Reis SAD, Carvalho MAD, De-Melo LDB. Galectin-3 mediates survival and apoptosis pathways during Trypanosoma cruzi-host cell interplay. Exp Parasitol 2020; 216:107932. [PMID: 32535113 DOI: 10.1016/j.exppara.2020.107932] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 05/21/2020] [Accepted: 05/25/2020] [Indexed: 12/18/2022]
Abstract
Neglected tropical diseases, such as Chagas disease caused by the protozoa Trypanosoma cruzi, affect millions of people worldwide but lack effective treatments that are accessible to the entire population, especially patients with the debilitating chronic phase. The recognition of host cells, invasion and its intracellular replicative success are essential stages for progression of the parasite life cycle and the development of Chagas disease. It is predicted that programmed cell death pathways (apoptosis) would be activated in infected cells, either via autocrine secretion or mediated by cytotoxic immune cells. This process should play a key role in resolving infections by hindering the evolutionary success of the parasite. In this research, we performed assays to investigate the role of the lectin galectin-3 (Gal3) in parasite-host signaling pathways. Using cells with endogenous levels of Gal3 compared to Gal3-deficient cells (induced by RNA interference), we demonstrated that T. cruzi mediated the survival pathways and the subverted apoptosis through Gal3 promoting a pro-survival state in infected cells. Infected Gal3-depleted cells showed increased activation of caspase 3 and pro-apoptotic targets, such as poly (ADP-ribose) polymerase (PARP), and lower accumulation of anti-apoptotic proteins, such as c-IAP1, survivin and XIAP. During the early stages of infection, Gal3 translocates from the cytoplasm to the nucleus and must act in survival pathways. In a murine model of experimental infection, Gal3 knockout macrophages showed lower infectivity and viability. In vivo infection revealed a lower parasitemia and longer survival and an increased spleen cellularity in Gal3 knockout mice with consequences on the percentage of T lymphocytes (CD4+ CD11b+) and macrophages. In addition, cytokines such as IL-2, IL-4, IL-6 and TNF-α are increased in Gal3 knockout mice when compared to wild type genotype. These data demonstrate a Gal3-mediated complex interplay in the host cell, keeping infected cells alive long enough for infection and intracellular proliferation of new parasites. However, a continuous knowledge of these signaling pathways should contribute to a better understanding the mechanisms of cell death subversion that are promoted by protozoans in the pathophysiology of neglected diseases such as Chagas disease.
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Affiliation(s)
- Michelle de Oliveira Chain
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cefas Augusto de Medeiros Paiva
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Igor Oliveira Maciel
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alberto Nogueira Neto
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vitória Fernandes de Castro
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Caroline Pacheco de Oliveira
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bruna Dos Santos Mendonça
- Cellular and Molecular Hemato-Oncology Laboratory, National Institute of Cancer, Rio de Janeiro, Brazil
| | - Gabriela Nestal de Moraes
- Cellular and Molecular Hemato-Oncology Laboratory, National Institute of Cancer, Rio de Janeiro, Brazil
| | - Sheila Albert Dos Reis
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcelo Alex de Carvalho
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Dione Barbosa De-Melo
- Molecular Genetics Laboratory, Federal Institute of Education, Science and Technology of Rio de Janeiro, Rio de Janeiro, Brazil.
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Inhibition of Galectin-3 Alleviates Cigarette Smoke Extract-Induced Autophagy and Dysfunction in Endothelial Progenitor Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:7252943. [PMID: 31737173 PMCID: PMC6815545 DOI: 10.1155/2019/7252943] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 08/06/2019] [Accepted: 08/13/2019] [Indexed: 01/05/2023]
Abstract
Endothelial progenitor cells (EPCs) have the potential to repair damaged blood vessels and promote angiogenesis. Smoking, an important risk factor for cardiovascular diseases, is associated with impaired functions of EPCs. However, the underlying mechanisms remain unclear. The aim of the study was to investigate the effects of cigarette smoke extract (CSE) on autophagy and dysfunction of EPCs and the involvement of galectin-3 in its effects. EPCs were treated with 8% CSE for 24 h (without affecting cell viability). EPC functions were assessed by tube formation and migration capacity and intracellular ROS and eNOS expression. Autophagy was assessed by autophagic protein expression by Western blotting and immunofluorescence microscopy and autophagosome accumulation by transmission electron microscopy. Galectin-3 expression was measured by real-time PCR, Western blotting, and immunofluorescence microscopy, while phospho-AMPK and phospho-mTOR were measured by Western blotting. EPCs were transfected by shRNA-Gal-3 or shRNA-NC before treatment with CSE to examine the effects of galectin-3 on CSE-induced autophagy and dysfunction of EPCs. CSE-treated EPCs showed decreased tube formation and migration ability and eNOS expression but increased oxidative stress. CSE also induced autophagy which was characterized by a decrease in p62 protein, an increase in LC3B-II/I ratio, and accumulation of autophagosomes. CSE upregulated galectin-3 expression on EPCs. Inhibition of galectin-3 abrogated CSE-induced autophagy and dysfunction of EPCs. CSE activated phospho-AMPK and inhibited phospho-mTOR, and inhibition of galectin-3 abolished CSE's effect on activating phospho-AMPK and inhibiting phospho-mTOR. In conclusion, our results suggest that galectin-3 mediates CSE-induced EPC autophagy and dysfunction, likely via the AMPK/mTOR signaling pathway.
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Decoding the sweet regulation of apoptosis: the role of glycosylation and galectins in apoptotic signaling pathways. Cell Death Differ 2019; 26:981-993. [PMID: 30903104 DOI: 10.1038/s41418-019-0317-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/02/2019] [Accepted: 02/25/2019] [Indexed: 12/17/2022] Open
Abstract
Glycosylation and glycan-binding proteins such as galectins play an important role in the control of cell death signaling. Strikingly, very little attention has been given so far to the understanding of the molecular details behind this key regulatory network. Glycans attached to the death receptors such as CD95 and TRAIL-Rs, either alone or in a complex with galectins, might promote or inhibit apoptotic signals. However, we have just started to decode the functions of galectins in the modulation of extrinsic and intrinsic apoptosis. In this work, we have discussed the current understanding of the glycosylation-galectin regulatory network in CD95- as well as TRAIL-R-induced apoptosis and therapeutic strategies based on targeting galectins in cancer.
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28
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Veena VS, George PS, Rajan K, Chandramohan K, Jayasree K, Sujathan K. Immunocytochemistry on Sputum Samples Predicts Prognosis of Lung Cancer. J Cytol 2019; 36:38-43. [PMID: 30745738 PMCID: PMC6343390 DOI: 10.4103/joc.joc_103_17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Context Despite sputum cytology being accepted as a simple and noninvasive diagnostic method for lung cancer, the clinical usefulness of sputum for evaluation of prognosis is yet to be explored. Validation of some of the markers in sputum for prognosis prediction will be highly useful for selective therapy. Aims This study was aimed to evaluate a reliable panel of immunocytochemical markers for their significance to predict survival. Materials and Methods We have analyzed the expression of p53, p16, galectin-3, and epidermal growth factor receptor (EGFR) proteins in sputum samples processed in a mucolytic agent/cellblock and compared the same with that of the corresponding tissue samples. Results Overexpression of p16 and EGFR was found to have a better survival benefit, whereas positive p53 and galectin-3 expressions had shorter period of survival. Expression patterns of all these four proteins were more or less similar in smears, cellblocks of sputum, and tissue samples except for slight changes in staining intensity which was not found to be statistically significant. No significant difference was found in the association of these proteins with survival pattern between sputum and tissue samples. Conclusion This is the first report of immunocytochemistry of a panel of markers on cells exfoliated in sputum samples which suggests that analysis of immunocytochemical markers in sputum samples can be attempted as a cost-effective and reliable predictor of prognosis and survival. Accumulation of mutated p53, overexpression of galectin-3, and lower expression of p16 and EGFR proteins were found to predict poor prognosis for lung cancer.
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Affiliation(s)
- V S Veena
- Division of Pathology, Regional Cancer Centre, Trivandrum, Kerala, India
| | - Preethi Sara George
- Division of Cancer Epidemiology, Regional Cancer Centre, Trivandrum, Kerala, India
| | - K Rajan
- Division of Respiratory Medicine, Medical College, Trivandrum, Kerala, India
| | - K Chandramohan
- Division of Surgical Oncology, Regional Cancer Centre, Trivandrum, Kerala, India
| | - K Jayasree
- Division of Pathology, Regional Cancer Centre, Trivandrum, Kerala, India
| | - K Sujathan
- Division of Cancer Research, Regional Cancer Centre, Trivandrum, Kerala, India
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Okamoto M, Hidaka A, Toyama M, Baba M. Galectin-3 is involved in HIV-1 expression through NF-κB activation and associated with Tat in latently infected cells. Virus Res 2018; 260:86-93. [PMID: 30481548 DOI: 10.1016/j.virusres.2018.11.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 09/12/2018] [Accepted: 11/23/2018] [Indexed: 12/13/2022]
Abstract
Galectin-3 (Gal-3) is involved in many biological processes and pathogenesis of diseases in part through nuclear factor (NF)-κB activation. We demonstrated that Gal-3 expression was significantly induced by tumor necrosis factor (TNF)-α or phorbol 12-myristate 13-acetate in OM-10.1 and ACH-2 cells, which are considered as a model of HIV-1 latently infected cells. The expression of Gal-3 was also associated with their viral production. However, the induction of Gal-3 by TNF-α was not observed in their uninfected parental cells. Knockdown of Gal-3 resulted in the suppression of NF-κB activation and HIV-1 replication in the latently infected cells. The expression level of Gal-3 was highly correlated with that of HIV-1 Tat in the latently infected cells stimulated with TNF-α. Furthermore, colocalization and possible interaction of Gal-3 and Tat were observed in the stimulated cells. These results suggent that Gal-3 expression is closely correlated with HIV-1 expression in latently infected cells through NF-κB activation and the interaction with Tat.
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Affiliation(s)
- Mika Okamoto
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, 890-8544, Japan
| | - Akemi Hidaka
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, 890-8544, Japan
| | - Masaaki Toyama
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, 890-8544, Japan
| | - Masanori Baba
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Kagoshima University, Kagoshima, 890-8544, Japan.
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Wang H, Song X, Huang Q, Xu T, Yun D, Wang Y, Hu L, Yan Y, Chen H, Lu D, Chen J. LGALS3 Promotes Treatment Resistance in Glioblastoma and Is Associated with Tumor Risk and Prognosis. Cancer Epidemiol Biomarkers Prev 2018; 28:760-769. [PMID: 30341098 DOI: 10.1158/1055-9965.epi-18-0638] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 07/28/2018] [Accepted: 10/15/2018] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND LGALS3 promotes tumor progression in diverse cancers. However, the involvement of LGALS3 in glioblastoma has not yet been broadly illuminated. METHODS Microarray was performed to detect the gene expression profiles of radioresistance in T98G cells and identified a universally upregulated gene, LGALS3. The impact of LGALS3 on the survival of glioblastoma cells facing ionizing irradiation or temozolomide was investigated by the Cell Counting Kit-8 (CCK-8). A total of 120 glioblastoma cases were collected to analyze the relationship between LGALS3 expression and patient prognosis. Another 961 patients with glioma and 1,351 healthy controls were recruited to study the association of SNPs across the LGALS3 gene with glioblastoma susceptibility. The functional SNP sites were also studied in cellular experiments. RESULTS An effective protection of LGALS3 from ionizing irradiation or temozolomide-induced cell death in T98G and U251 cells was found. In addition, high expression of LGALS3 could work as an independent risk factor for survival of patients with glioblastoma. Two SNP sites (rs4644 and rs4652) across the LGALS3 gene were associated with increased risk for glioblastoma, and the C allele of rs4652 and the A allele of rs4644 could enhance glioblastoma resistance to radio-chemotherapy, but not cell proliferation. CONCLUSIONS Our results suggest that LGALS3 is an important biomarker influencing glioblastoma risk and prognosis and a potential target for treating the malignancy, especially ones with resistance against the standard therapy. IMPACT LGALS3 promotes glioblastoma cells' resistance to ionizing irradiation and temozolomide and predicts poor prognosis. Targeting LGALS3 may limit the therapeutic resistance in glioblastoma and increase patient survival.
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Affiliation(s)
- Hongxiang Wang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Xiao Song
- Department of Thoracic Surgery, Lung Cancer Diagnosis and Treatment Center, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China
| | - Qilin Huang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Tao Xu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dapeng Yun
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuqi Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Lingna Hu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yong Yan
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Hongyan Chen
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Daru Lu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
| | - Juxiang Chen
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
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31
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Huang CS, Tang SJ, Lee MH, Chang Wang CC, Sun GH, Sun KH. Galectin-3 promotes CXCR2 to augment the stem-like property of renal cell carcinoma. J Cell Mol Med 2018; 22:5909-5918. [PMID: 30246456 PMCID: PMC6237593 DOI: 10.1111/jcmm.13860] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 07/03/2018] [Accepted: 07/24/2018] [Indexed: 11/28/2022] Open
Abstract
Although targeted therapy is usually the first‐line treatment for advanced renal cell carcinoma (RCC), some patients can experience drug resistance. Cancer stem cells are tumour‐initiating cells that play a vital role in drug resistance, metastasis and cancer relapse, while galectins (Gal) participate in tumour progression and drug resistance. However, the exact role of galectins in RCC stemness is yet unknown. In this study, we grew a subpopulation of RCC cells as tumour spheres with higher levels of stemness‐related genes, such as Oct4, Sox2 and Nanog. Among the Gal family, Gal‐3 in particular was highly expressed in RCC tumour spheres. To further investigate Gal‐3's role in the stemness of RCC, lentivirus‐mediated knockdown and overexpression of Gal‐3 in RCC cells were used to examine both in vitro and in vivo tumorigenicity. We further assessed Gal‐3 expression in RCC tissue microarray using immunohistochemistry. Upon suppressing Gal‐3 in parental RCC cells, invasion, colony formation, sphere‐forming ability, drug resistance and stemness‐related gene expression were all significantly decreased. Furthermore, CXCL6, CXCL7 and CXCR2 were down‐regulated in Gal‐3‐knockdown tumour spheres, while CXCR2 overexpression in Gal‐3‐knockdown RCC restored the ability of sphere formation. Gal‐3 overexpression in RCC promoted both in vitro and in vivo tumorigenicity, and its expression was correlated with CXCR2 expression and tumour progression in clinical tissues. RCC patients with higher co‐expressions of Gal‐3 and CXCR2 demonstrated a worse survival rate. These results indicate that highly expressed Gal‐3 may up‐regulate CXCR2 to augment RCC stemness. Gal‐3 may be a prognostic and innovative target of combined therapy for treating RCC.
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Affiliation(s)
- Chang-Shuo Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shye-Jye Tang
- Institute of Marine Biotechnology, National Taiwan Ocean University, Keelung, Taiwan
| | - Mei-Hsuan Lee
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Chih Chang Wang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Guang-Huan Sun
- Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan
| | - Kuang-Hui Sun
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
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32
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Ruvolo PP. Galectins as regulators of cell survival in the leukemia niche. Adv Biol Regul 2018; 71:41-54. [PMID: 30245264 DOI: 10.1016/j.jbior.2018.09.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 02/08/2023]
Abstract
The microenvironment within the bone marrow (BM) contains support cells that promote leukemia cell survival and suppress host anti-tumor defenses. Galectins are a family of beta-galactoside binding proteins that are critical components in the tumor microenvironment. Galectin 1 (LGALS1) and Galectin 3 (LGALS3) as regulators of RAS signaling intracellularly and as inhibitors of immune cells extracellularly are perhaps the best studied members for their role in leukemia biology. Interest in Galectin 9 (LGALS9) is growing as this galectin has been identified as an immune checkpoint molecule. LGALS9 also supports leukemia stem cells (LSCs) though a mechanism of action is not clear. LGALS1 and LGALS3 each participate in a diverse number of survival pathways that promote drug resistance by supporting pro-tumor molecules such BCL2, MCL-1, and MYC and blocking tumor suppressors like p53. Acute myeloid leukemia (AML) BM mesenchymal stromal cells (MSC) have protein signatures that differ from healthy donor MSC. Elevated LGALS3 protein in AML MSC is associated with refractory disease/relapse demonstrating that MSC derived galectin impacts patient survival. LGALS3 is a critical determining factor whether MSC differentiate into adipocytes or osteoblasts so the galectin influences the cellular composition of the leukemia niche. Both LGALS3 and LGALS1 when secreted can suppress immune function. Both galectins can induce apoptosis of T cells. LGALS3 also modulates T cell receptor endocytosis and impairs interferon mediated chemokine production by binding glycosylated interferon. LGALS3 as a TIM3 binding partner acts to suppress T cell function. Galectins also impact leukemia cell mobilization and may participate in homing mechanisms. LGALS3 participates in transport mechanism of integrins, receptors, and other molecules that control cell adhesion and cell:cell interactions. The diversity of these various functions demonstrate the importance of these galectins in the leukemia niche. This review will cover the role of LGALS1, LGALS3, and LGALS9 in the various processes that are critical for maintaining leukemia cells in the tumor microenvironment.
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Affiliation(s)
- Peter P Ruvolo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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33
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Santarsia S, Grosso AS, Trovão F, Jiménez-Barbero J, Carvalho AL, Nativi C, Marcelo F. Molecular Recognition of a Thomsen-Friedenreich Antigen Mimetic Targeting Human Galectin-3. ChemMedChem 2018; 13:2030-2036. [PMID: 30094951 DOI: 10.1002/cmdc.201800525] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Indexed: 11/11/2022]
Abstract
Overexpression of the Thomsen-Friedenreich (TF) antigen in cell membrane proteins occurs in 90 % of adenocarcinomas. Additionally, the binding of the TF antigen to human galectin-3 (Gal-3), also frequently overexpressed in malignancy, promotes cancer progression and metastasis. In this context, structures that interfere with this specific interaction have the potential to prevent cancer metastasis. A multidisciplinary approach combining the optimized synthesis of a TF antigen mimetic with NMR, X-ray crystallography methods, and isothermal titration calorimetry assays was used to unravel the molecular structural details that govern the Gal-3/TF mimetic interaction. The TF mimetic has a binding affinity for Gal-3 similar to that of the TF natural antigen and retains the binding epitope and bioactive conformation observed for the native antigen. Furthermore, from a thermodynamic perspective, a decrease in the enthalpic contribution was observed for the Gal-3/TF mimetic complex; however, this behavior is compensated by a favorable gain in entropy. From a structural perspective, these results establish our TF mimetic as a scaffold to design multivalent solutions to potentially interfere with Gal-3 aberrant interactions and for likely use in hampering Gal-3-mediated cancer cell adhesion and metastasis.
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Affiliation(s)
- Sabrina Santarsia
- Department of Chemistry Ugo Schiff, University of Florence, Via della Lastruccia, 13-50019, Sesto Fiorentino, Italy
| | - Ana Sofia Grosso
- UCIBIO, REQUIMTE, Departamento de Química, Faculdade De Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal
| | - Filipa Trovão
- UCIBIO, REQUIMTE, Departamento de Química, Faculdade De Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal
| | - Jesús Jiménez-Barbero
- CIC-bioGUNE Bizkaia, 48160, Derio, Spain.,Ikerbasque, Basque Foundation for Science, 48005, Bilbao, Spain.,Department of Organic Chemistry II, EHU-UPV, 48040, Leioa, Spain
| | - Ana Luísa Carvalho
- UCIBIO, REQUIMTE, Departamento de Química, Faculdade De Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal
| | - Cristina Nativi
- Department of Chemistry Ugo Schiff, University of Florence, Via della Lastruccia, 13-50019, Sesto Fiorentino, Italy
| | - Filipa Marcelo
- UCIBIO, REQUIMTE, Departamento de Química, Faculdade De Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal
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34
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Maghathe T, Miller WK, Mugge L, Mansour TR, Schroeder J. Immunotherapy and potential molecular targets for the treatment of pituitary adenomas resistant to standard therapy: a critical review of potential therapeutic targets and current developments. J Neurosurg Sci 2018; 64:71-83. [PMID: 30014686 DOI: 10.23736/s0390-5616.18.04419-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Pituitary adenomas (PAs) are primary central nervous system (CNS) tumors, accounting for as much as 25% of intracranial neoplasms. Although existing remedies show success in treating most PAs, treatment of invasive and non-functioning PAs, in addition to functioning PAs unresponsive to standard therapy, remains challenging. With the continually increasing understanding of biochemical pathways involved in tumorigenesis, immunotherapy stands as a promising alternative therapy for pituitary tumors that are resistant to standard therapy. EVIDENCE ACQUISITION A literature search was conducted of the PubMed database for immunotherapies of PAs. The search yielded a total of 2621 articles, 26 of which were included in our discussion. EVIDENCE SYNTHESIS Several pathologically expressed molecules could potentially serve as promising targets of current or future immunotherapies for PAs. Programmed death ligand-1, matrix metalloproteinases, EpCAM (Trop1) and Trop2, cancer-testis antigen MAGE-A3, epidermal growth factor receptor (EGFR), folate receptor alpha, vascular endothelial growth factor, and galectin-3 have all been implicated as crucial factors involved with tumor survival and invasion. Inhibition of these pathways may prove efficacious in the management of invasive and treatment-resistant PAs. CONCLUSIONS Rapid advancements in tumor immunology may increase the probability of successful treatment of PAs by exploitation of the normal immune response or by targeting novel proteins. Current research on many of the targets reviewed in this article are successfully being utilized to manage various neoplastic disease including CNS tumors. These therapies may eventually play a key role in the treatment of PAs that do not respond to standard therapy.
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Affiliation(s)
- Tamara Maghathe
- Division of Neurosurgery, Department of Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - William K Miller
- Division of Neurosurgery, Department of Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - Luke Mugge
- Division of Neurosurgery, Department of Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - Tarek R Mansour
- Division of Neurosurgery, Department of Surgery, University of Toledo Medical Center, Toledo, OH, USA
| | - Jason Schroeder
- Division of Neurosurgery, Department of Surgery, University of Toledo Medical Center, Toledo, OH, USA -
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35
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Ruvolo PP, Ruvolo VR, Burks JK, Qiu Y, Wang RY, Shpall EJ, Mirandola L, Hail N, Zeng Z, McQueen T, Daver N, Post SM, Chiriva-Internati M, Kornblau SM, Andreeff M. Role of MSC-derived galectin 3 in the AML microenvironment. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2018; 1865:959-969. [PMID: 29655803 PMCID: PMC5936474 DOI: 10.1016/j.bbamcr.2018.04.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 04/09/2018] [Accepted: 04/10/2018] [Indexed: 12/16/2022]
Abstract
In acute myeloid leukemia (AML), high Galectin 3 (LGALS3) expression is associated with poor prognosis. The role of LGALS3 derived from mesenchymal stromal cells (MSC) in the AML microenvironment is unclear; however, we have recently found high LGALS3 expression in MSC derived from AML patients is associated with relapse. In this study, we used reverse phase protein analysis (RPPA) to correlate LGALS3 expression in AML MSC with 119 other proteins including variants of these proteins such as phosphorylated forms or cleaved forms to identify biologically relevant pathways. RPPA revealed that LGALS3 protein was positively correlated with expression of thirteen proteins including MYC, phosphorylated beta-Catenin (p-CTNNB1), and AKT2 and negatively correlated with expression of six proteins including integrin beta 3 (ITGB3). String analysis revealed that proteins positively correlated with LGALS3 showed strong interconnectivity. Consistent with the RPPA results, LGALS3 suppression by shRNA in MSC resulted in decreased MYC and AKT expression while ITGB3 was induced. In co-culture, the ability of AML cell to adhere to MSC LGALS3 shRNA transductants was reduced compared to AML cell adhesion to MSC control shRNA transductants. Finally, use of novel specific LGALS3 inhibitor CBP.001 in co-culture of AML cells with MSC reduced viable leukemia cell populations with induced apoptosis and augmented the chemotherapeutic effect of AraC. In summary, the current study demonstrates that MSC-derived LGALS3 may be critical for important biological pathways for MSC homeostasis and for regulating AML cell localization and survival in the leukemia microenvironmental niche.
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Affiliation(s)
- Peter P Ruvolo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States.
| | - Vivian R Ruvolo
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jared K Burks
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - YiHua Qiu
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rui-Yu Wang
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Elizabeth J Shpall
- Department of Stem Cell Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | | | - Numsen Hail
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Zhihong Zeng
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Teresa McQueen
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Naval Daver
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Sean M Post
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Maurizio Chiriva-Internati
- Kiromic Biopharma, Houston, TX, United States; Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Steven M Kornblau
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Michael Andreeff
- Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Section of Molecular Hematology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
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36
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Aboulhagag NA, El-Deek HEM, Sherif MF. Expression of galectin-1 and galectin-3 in renal cell carcinoma; immunohistochemical study. Ann Diagn Pathol 2018; 36:31-37. [PMID: 30055522 DOI: 10.1016/j.anndiagpath.2018.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 05/18/2018] [Accepted: 06/20/2018] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS Galectins comprise a large family of calcium independent lectins. Galectin-1 and galectin-3 contribute to neoplastic transformation, angiogenesis, and tumor metastasis in some cancers. This study aimed at studying the immunohistochemical expression of both galectin-1 and galectin-3 in renal cell carcinoma (RCC) variants and detecting the possible association of galectins with various clinicopathological parameters. MATERIALS AND METHODS Sections from 67 formalin-fixed paraffin-embedded tissue blocks of RCC variants were stained with galectin-1 and galectin-3. Expression was assessed in tumor tissue and adjacent renal parenchyma and was correlated with clinicopathological criteria. RESULTS In apparently normal renal parenchyma adjacent to tumor tissue, galectin-1 was expressed in 27 (40.2%) of specimens in renal tubules and glomeruli, while 34 (50.7%) of specimens showed galectin-3 expression in renal tubules sparing glomeruli. In tumor tissue, galectin-1 showed high expression in 47 (70.1%) and low expression in 20 (29.9%) of specimens. Galectin-3 had high expression in 15 (22.4%) and low expression in 52 (77.6%) of specimens. Significant association was detected between expression of galectin-1 and galectin-3 and the type of RCC (P = 0.032) and (P = 0.006), respectively. Significant inverse association was detected between the expression of galectin-3 and the presence of tumor haemorrhage and necrosis (P = 0.014) and (P = 0.039), respectively. CONCLUSION Galectin-1 and galectin-3 are overexpressed in RCC with different percentage in different subtypes. Galactin-1expression is more in tumor tissue than surrounding renal parenchyma suggesting that it has a carcinogenic role. Galectin-1 and galectin-3 overexpression in chromophobe RCC suggests that they may have diagnostic role.
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Affiliation(s)
- Noha A Aboulhagag
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Heba E M El-Deek
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud F Sherif
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
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37
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The N-terminal tail coordinates with carbohydrate recognition domain to mediate galectin-3 induced apoptosis in T cells. Oncotarget 2018; 8:49824-49838. [PMID: 28548942 PMCID: PMC5564810 DOI: 10.18632/oncotarget.17760] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 04/24/2017] [Indexed: 12/14/2022] Open
Abstract
Galectin-3 is a galectin with a unique flexible N-terminal tail (NT) connected to the conserved carbohydrate recognition domain (CRD). Galectin-3 is associated with tumor immune tolerance and exhibits an ability to induce T cell apoptosis. We used Jurkat, Jurkat E6-1 and CEM T-cell lines and human peripheral blood mononuclear cells (PBMCs) to investigate the specific roles of the CRD and NT in inducing T cell apoptosis. Galectin-3 triggered sustained extracellular signal-regulated kinase (ERK) phosphorylation that induced apoptosis. ERK was situated upstream of caspase-9 and was independently activated by reactive oxygen species (ROS) and protein kinase C (PKC). The first twelve NT residues had no role in the apoptosis. Residues 13-68 were essential for activating ROS, but did not activate PKC. However, residues 69-110 were required for activation of PKC. An NT fragment and a NT-specific antibody antagonized the apoptosis triggered by full-length galectin-3 further supporting our findings. These findings indicate the CRD and NT play important roles during induction of T cell apoptosis, which suggests their potential as therapeutic targets for reversing cancer immune tolerance.
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38
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Gao X, Liu J, Liu X, Li L, Zheng J. Cleavage and phosphorylation: important post-translational modifications of galectin-3. Cancer Metastasis Rev 2018; 36:367-374. [PMID: 28378189 DOI: 10.1007/s10555-017-9666-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
As the unique chimeric member of the β-galactoside-binding protein family, galectin-3 is a multivalent and multifunctional oncogenic protein involved in multiple physiological and pathological processes, including cell growth, cell differentiation, cell adhesion, RNA splicing, cell apoptosis, and malignant transformation. Post-translational modifications can effectively increase a protein's functional diversity, either by degradation or adding chemical modifications, thus regulating activity, localization, and ligand interaction. In order to clearly understand the functional mechanisms of galectin-3 involved in normal cell biology and pathogenesis, here, we have summarized the previously reported post-translational modifications of galectin-3, including cleavage and phosphorylation. Cleavage of galectin-3 by MMPs, PSA, and proteases from parasites generated intact carbohydrate-recognition domain and N-terminal peptides of varying lengths that retained lectin binding activity but lost multivalence. Serine and tyrosine phosphorylation of galectin-3 by c-Abl, CKI, and GSK-3β could regulate its localization and associated signal transduction. Accordingly, cleavage and phosphorylation play an important role in regulating galectin-3 function via altering its multivalence, localization, and ligand interaction.
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Affiliation(s)
- Xiaoge Gao
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Jingjie Liu
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Xiangye Liu
- Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221004, People's Republic of China
| | - Liantao Li
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China
| | - Junnian Zheng
- Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China. .,Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China. .,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, People's Republic of China.
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39
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Gao J, Li T, Mo Z, Hu Y, Yi Q, He R, Zhu X, Zhou X, She S, Chen Y. Overexpression of the galectin-3 during tumor progression in prostate cancer and its clinical implications. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2018; 11:839-846. [PMID: 31938173 PMCID: PMC6958038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Accepted: 11/13/2017] [Indexed: 06/10/2023]
Abstract
Management of prostate cancer, especially advanced prostate cancer, remains clinically challenging and requires the identification of new biomarkers and therapeutic targets that can be exploited to improve patient outcome. Galectin-3 (gal-3) is a carbohydrate-binding protein involved in cancer progression and metastasis, including prostate tissues. Gal-3 function is regulated by proteolytic cleavage and the cleaved gal-3 is implicated in tumor progression. This study is the first to determine gal-3 expressions with two monoclonal anti-gal-3 antibodies in prostate tissues to distinguish expression patterns between intact and cleaved gal-3 and analyze their clinical relevance. Our results showed gal-3 cleavage occurred in prostate cancer but not normal prostate. Gal-3 presented in tumor tissues was mainly the cleaved form that can be detected by the anti-gal-3 antibody targeting C terminal. The cleaved gal-3, but not the intact gal-3, was increased in prostate cancer compared to normal prostate tissues and positively associated with malignance, tumor progression and metastasis. In addition, the expression of cleaved gal-3 was closely related to PSA level, indicating a PSA-mediated degradation of intact gal-3 in prostate cancer. In summary, our findings suggested the cleaved gal-3 could be a valuable diagnostic biomarker and a therapeutic target for the treatment of prostate cancer, especially advanced metastatic prostate cancer.
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Affiliation(s)
- Jiamin Gao
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Tianyu Li
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Department of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
| | - Zengnan Mo
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Department of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Yanling Hu
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Qiaoyong Yi
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Rongquan He
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Xiujuan Zhu
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Xianguo Zhou
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
| | - Shangyang She
- Clinical Laboratory, Guangxi Maternal and Child Health HospitalNanning, Guangxi Zhuang Autonomous Region, China
| | - Yingchun Chen
- Center for Genomic and Personalized Medicine, Guangxi Medical UniversityNanning, Guangxi Zhuang Autonomous Region, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized MedicineNanning, Guangxi Zhuang Autonomous Region, China
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40
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Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, Bellotti C, Salehi LB, Ricci A. Galectin-3: One Molecule for an Alphabet of Diseases, from A to Z. Int J Mol Sci 2018; 19:ijms19020379. [PMID: 29373564 PMCID: PMC5855601 DOI: 10.3390/ijms19020379] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 01/18/2018] [Accepted: 01/22/2018] [Indexed: 02/07/2023] Open
Abstract
Galectin-3 (Gal-3) regulates basic cellular functions such as cell-cell and cell-matrix interactions, growth, proliferation, differentiation, and inflammation. It is not surprising, therefore, that this protein is involved in the pathogenesis of many relevant human diseases, including cancer, fibrosis, chronic inflammation and scarring affecting many different tissues. The papers published in the literature have progressively increased in number during the last decades, testifying the great interest given to this protein by numerous researchers involved in many different clinical contexts. Considering the crucial role exerted by Gal-3 in many different clinical conditions, Gal-3 is emerging as a new diagnostic, prognostic biomarker and as a new promising therapeutic target. The current review aims to extensively examine the studies published so far on the role of Gal-3 in all the clinical conditions and diseases, listed in alphabetical order, where it was analyzed.
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Affiliation(s)
- Salvatore Sciacchitano
- Department of Clinical and Molecular Medicine, Sapienza University, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
| | - Luca Lavra
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
| | - Alessandra Morgante
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
| | - Alessandra Ulivieri
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
| | - Fiorenza Magi
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
| | - Gian Paolo De Francesco
- Department of Oncological Science, Breast Unit, St Andrea University Hospital, Via di Grottarossa, 1035/39, 00189 Rome, Italy.
| | - Carlo Bellotti
- Operative Unit Surgery of Thyroid and Parathyroid, Sapienza University of Rome, S. Andrea Hospital, Via di Grottarossa, 1035/39, 00189 Rome, Italy.
| | - Leila B Salehi
- Laboratory of Biomedical Research, Niccolò Cusano University Foundation, Via Don Carlo Gnocchi 3, 00166 Rome, Italy.
- Department of Biopathology and Diagnostic Imaging, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy.
| | - Alberto Ricci
- Department of Clinical and Molecular Medicine, Sapienza University, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
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Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives. Int J Mol Sci 2018; 19:ijms19010210. [PMID: 29320431 PMCID: PMC5796159 DOI: 10.3390/ijms19010210] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/23/2017] [Accepted: 12/28/2017] [Indexed: 12/13/2022] Open
Abstract
The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for β-galactosides. The galectin–glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins’ action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.
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Shi Y, Lin X, Chen G, Yan J, Ying M, Zheng X. Galectin-3 rs4652 A>C polymorphism is associated with the risk of gastric carcinoma and P-glycoprotein expression level. Oncol Lett 2017; 14:8144-8149. [PMID: 29250191 DOI: 10.3892/ol.2017.7258] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 09/01/2017] [Indexed: 01/19/2023] Open
Abstract
Galectin-3 serves an important function in cancer development and progression. The present study aimed to explore the association between single nucleotide polymorphisms in galectin-3, and the susceptibility to chemotherapy drug resistance of gastric carcinoma. The present study was a case-control study including 479 patients with gastric carcinoma and 458 cancer-free controls in a population from the Fujian province in Southeast China. Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry was used to determine the genotype of rs4644 and rs4652, and immunohistochemistry was used to identify the expression level of various proteins associated with chemotherapeutic drug resistance. The results revealed that individuals exhibiting the rs4652 CA/AA genotype had a significantly increased risk of developing gastric carcinoma compared with the rs4652 CC genotype (adjusted odds ratio, 1.51; 95% confidence interval, 1.05-2.18; adjusted P=0.03). In addition, it was demonstrated that there were significant differences in the P-glycoprotein expression level depending on rs4652 genotypic distributions (χ2=9.063; P=0.028). Therefore, the present study demonstrated that rs4652 single nucleotide polymorphisms of the galectin-3 gene contribute to the susceptibility to and chemotherapeutic drug resistance of gastric carcinoma.
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Affiliation(s)
- Yi Shi
- Department of Molecular Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Xiandong Lin
- Department of Molecular Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Gang Chen
- Department of Molecular Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China.,Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Jun Yan
- Department of Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Mingang Ying
- Department of Surgery, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Xiongwei Zheng
- Department of Molecular Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China.,Department of Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
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Hosoda M, Akune Y, Aoki-Kinoshita KF. Development and application of an algorithm to compute weighted multiple glycan alignments. Bioinformatics 2017; 33:1317-1323. [PMID: 28093404 PMCID: PMC5408794 DOI: 10.1093/bioinformatics/btw827] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 12/22/2016] [Accepted: 01/10/2017] [Indexed: 11/13/2022] Open
Abstract
Motivation A glycan consists of monosaccharides linked by glycosidic bonds, has branches and forms complex molecular structures. Databases have been developed to store large amounts of glycan-binding experiments, including glycan arrays with glycan-binding proteins. However, there are few bioinformatics techniques to analyze large amounts of data for glycans because there are few tools that can handle the complexity of glycan structures. Thus, we have developed the MCAW (Multiple Carbohydrate Alignment with Weights) tool that can align multiple glycan structures, to aid in the understanding of their function as binding recognition molecules. Results We have described in detail the first algorithm to perform multiple glycan alignments by modeling glycans as trees. To test our tool, we prepared several data sets, and as a result, we found that the glycan motif could be successfully aligned without any prior knowledge applied to the tool, and the known recognition binding sites of glycans could be aligned at a high rate amongst all our datasets tested. We thus claim that our tool is able to find meaningful glycan recognition and binding patterns using data obtained by glycan-binding experiments. The development and availability of an effective multiple glycan alignment tool opens possibilities for many other glycoinformatics analysis, making this work a big step towards furthering glycomics analysis. Availability and Implementation http://www.rings.t.soka.ac.jp. Contact kkiyoko@soka.ac.jp. Supplementary information Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Masae Hosoda
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Tokyo, Japan
| | - Yukie Akune
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Tokyo, Japan
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Anastasi E, Gigli S, Santulli M, Tartaglione S, Ballesio L, Porpora MG, Granato T, Catalano C, Angeloni A, Manganaro L. Role of Galectin-3 Combined with Multi- Detector Contrast Enhanced Computed Tomography in Predicting Disease Recurrence in Patients with Ovarian Cancer. Asian Pac J Cancer Prev 2017; 18:1277-1282. [PMID: 28610414 PMCID: PMC5555535 DOI: 10.22034/apjcp.2017.18.5.1277] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Galectin-3 (Gal-3) is an endogenous β-galactoside-binding lectin, playing an important role in the pathogenesis of multiple malignancies. Aim of the study was to evaluate in a group of patients treated for ovarian cancer (EOC), the role of Gal-3 combined with multi-detector contrast-enhanced computed tomography (MDCT), as predictor of recurrence disease. Seventeen follow-up patients with recurrent ovarian cancer and 13 follow-up patients with stable ovarian disease, who performed MDCT at one-year follow-up after cytoreductive treatment, were enrolled. Serum Gal-3 concentrations were determined by using ELISA method. Twenty healthy controls were included in the analysis. Two radiologist blinded to patients status, reviewed MDCT exams, recording the following signs of disease recurrence: local tumor spread, enlarged lymph-nodes, carcinomatosis implants and metastases. We calculated the respective threshold values of Gal-3 identified by ROC curve analysis for each imaging findings related to disease recurrence: lymphoadenopathies 92.45 ng/ml (AUC: 0.81, Se=91% Spe=73%), carcinomatosis 85.95 ng/ml (AUC: 0.93 Se= 93.7%, Spe=92.8%), local tumor spread 99.05 (AUC: 0.90, Se=100%, Spe=73%) and metastasis 99.05ng/ml (AUC: 0,78, Se=100%, Spe=70%). A significant correlation between high Gal-3 serum levels and presence of local tumor spread (n=11/17, p:0.001), carcinomatosis (n=16/17, p:0.00), lymphoadenopathies (n=15/17, p:0.00) and metastasis (n=11/17, p:0.003) related with recurrence disease was observed. Patients with recurrence of ovarian cancer presents higher Gal-3 values compared to women with stable diseases. Gal-3 combined to CECT should be used to improve the monitoring of EOC patients.
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Affiliation(s)
- Emanuela Anastasi
- Department of Molecular Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
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Kolben TM, Kraft F, Kolben T, Goess C, Semmlinger A, Dannecker C, Schmoeckel E, Mayr D, Sommer NN, Mahner S, Jeschke U. Expression of Sialyl Lewis a, Sialyl Lewis x, Lewis y, Gal-3, Gal-7, STMN1 and p16 in cervical dysplasia. Future Oncol 2016; 13:145-157. [PMID: 27646625 DOI: 10.2217/fon-2016-0259] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
AIM Cervical intraepithelial neoplasia (CIN) is commonly divided into three grades. Guidelines increasingly recommend surgery only in CIN 3 lesions. We investigated markers to evaluate differences in CIN 2 and 3 lesions as well as possible predictors for regression/progression in CIN 2 lesions. MATERIALS & METHODS Biopsies (n = 128) of healthy cervical tissue and CIN 1-3 were stained for Sialyl Lewis a, Sialyl Lewis x, Lewis y, Gal-3, Gal-7, STMN1 and p16. RESULTS We observed significant differences between CIN 2 and 3 lesions for Sialyl Lewis a, Sialyl Lewis x, Gal-3, Gal-7, STMN1 and p16. Expression of Sialyl Lewis a was significantly higher in CIN 2 patients who progressed during follow-up. CONCLUSION Significant differences in marker expression support the differentiation of CIN 2 and 3. Lewis a may help to predict progression/regression in CIN 2 patients.
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Affiliation(s)
- Theresa M Kolben
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Franziska Kraft
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Thomas Kolben
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Christine Goess
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Anna Semmlinger
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Christian Dannecker
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Elisa Schmoeckel
- Department of Pathology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 27, 81377, Munich, Germany
| | - Doris Mayr
- Department of Pathology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 27, 81377, Munich, Germany
| | - Nora N Sommer
- Institute for Clinical Radiology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Sven Mahner
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
| | - Udo Jeschke
- Department for Obstetrics & Gynecology, University Hospital of Munich, Ludwig-Maximilians-University, Marchioninistr. 15, 81377, Munich, Germany
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Ilmer M, Mazurek N, Byrd JC, Ramirez K, Hafley M, Alt E, Vykoukal J, Bresalier RS. Cell surface galectin-3 defines a subset of chemoresistant gastrointestinal tumor-initiating cancer cells with heightened stem cell characteristics. Cell Death Dis 2016; 7:e2337. [PMID: 27512958 PMCID: PMC5108324 DOI: 10.1038/cddis.2016.239] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 06/13/2016] [Accepted: 07/08/2016] [Indexed: 12/12/2022]
Abstract
Recurrence of gastrointestinal adenocarcinomas after surgery and chemotherapy may be attributed, in part, to the presence of a small population of tumor-initiating cancer stem cells (CSC). The expression of galectin-3 (Gal3), a multifunctional oncolectin, has been associated with biological behaviors associated with CSC. We examined the ability of Gal3 to characterize the CSC phenotype, and to identify a clinically important gastrointestinal cancer CSC population. Human colorectal and pancreatic cancer cell lines were sorted to identify subpopulations expressing commonly used CSC markers, and Gal3-positive CSC subpopulations. The association of Gal3 with the stem cell properties and alterations of these phenotypes by manipulation of Gal3 expression was examined. Gastrointestinal cancer cell lines contain both Gal3-positive and Gal3-negative subpopulations. Gal3-positive CSCs are characterized by high ALDH activity, enhanced self-renewal ability in vitro (sphere formation) and tumor forming ability in vivo, and resistance to chemotherapeutic agents and death-receptor-mediated apoptosis compared to Gal3-negative CSCs. Silencing Gal3 modifies this behavior. Cell surface Gal3 expression identifies a subset of CSCs in gastrointestinal cancers with high levels of stem cell characteristics, including chemoresistance. This may provide a platform for developing treatment strategies that target CSC.
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Affiliation(s)
- Matthias Ilmer
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Nachman Mazurek
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - James C Byrd
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Karen Ramirez
- Department of Stem Cell Transplantation and Cellular Therapies, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Margarete Hafley
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Eckhard Alt
- Department of Medicine, Tulane University Health Science Center, New Orleans, LA USA
| | - Jody Vykoukal
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Robert S Bresalier
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX USA
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Cagnoni AJ, Pérez Sáez JM, Rabinovich GA, Mariño KV. Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer. Front Oncol 2016; 6:109. [PMID: 27242953 PMCID: PMC4865499 DOI: 10.3389/fonc.2016.00109] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/18/2016] [Indexed: 12/25/2022] Open
Abstract
Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin–glycan interactions.
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Affiliation(s)
- Alejandro J Cagnoni
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Juan M Pérez Sáez
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Buenos Aires , Argentina
| | - Gabriel A Rabinovich
- Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Karina V Mariño
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Buenos Aires , Argentina
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Blaževitš O, Mideksa YG, Šolman M, Ligabue A, Ariotti N, Nakhaeizadeh H, Fansa EK, Papageorgiou AC, Wittinghofer A, Ahmadian MR, Abankwa D. Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering. Sci Rep 2016; 6:24165. [PMID: 27087647 PMCID: PMC4834570 DOI: 10.1038/srep24165] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 03/22/2016] [Indexed: 12/12/2022] Open
Abstract
Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling.
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Affiliation(s)
- Olga Blaževitš
- Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland
| | - Yonatan G. Mideksa
- Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland
| | - Maja Šolman
- Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland
| | - Alessio Ligabue
- Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland
| | - Nicholas Ariotti
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Hossein Nakhaeizadeh
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Eyad K. Fansa
- Max Planck Institute for Molecular Physiology, 44227 Dortmund, Germany
| | | | | | - Mohammad R. Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Daniel Abankwa
- Turku Centre for Biotechnology, Åbo Akademi University, Tykistökatu 6B, 20520 Turku, Finland
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Pokrywka M, Bubka M, Janik M, Pocheć E, Hoja-Łukowicz D, Lityńska A. Gal-3 does not suppress cisplatin-induced apoptosis in A-375 melanoma cells. Cell Biol Int 2016; 40:428-38. [DOI: 10.1002/cbin.10582] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 01/20/2016] [Indexed: 01/18/2023]
Affiliation(s)
- Małgorzata Pokrywka
- Chair of Clinical Biochemistry; Jagiellonian University Medical College; Kopernika 15A 31-501 Kraków Poland
- Malopolska Centre of Biotechnology; Jagiellonian University; Gronostajowa 7A 30-387 Kraków Poland
| | - Monika Bubka
- Department of Glycoconjugate Biochemistry, Institute of Zoology; Jagiellonian University; Gronostajowa 9 30-387 Kraków Poland
| | - Marcelina Janik
- Department of Glycoconjugate Biochemistry, Institute of Zoology; Jagiellonian University; Gronostajowa 9 30-387 Kraków Poland
| | - Ewa Pocheć
- Department of Glycoconjugate Biochemistry, Institute of Zoology; Jagiellonian University; Gronostajowa 9 30-387 Kraków Poland
| | - Dorota Hoja-Łukowicz
- Department of Glycoconjugate Biochemistry, Institute of Zoology; Jagiellonian University; Gronostajowa 9 30-387 Kraków Poland
| | - Anna Lityńska
- Department of Glycoconjugate Biochemistry, Institute of Zoology; Jagiellonian University; Gronostajowa 9 30-387 Kraków Poland
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Bum-Erdene K, Leffler H, Nilsson UJ, Blanchard H. Structural characterisation of human galectin-4 N-terminal carbohydrate recognition domain in complex with glycerol, lactose, 3'-sulfo-lactose, and 2'-fucosyllactose. Sci Rep 2016; 6:20289. [PMID: 26828567 PMCID: PMC4734333 DOI: 10.1038/srep20289] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/30/2015] [Indexed: 01/02/2023] Open
Abstract
Galectin-4 is a tandem-repeat galectin with two distinct carbohydrate recognition domains (CRD). Galectin-4 is expressed mainly in the alimentary tract and is proposed to function as a lipid raft and adherens junction stabilizer by its glycan cross-linking capacity. Galectin-4 plays divergent roles in cancer and inflammatory conditions, either promoting or inhibiting each disease progression, depending on the specific pathological condition. The study of galectin-4's ligand-binding profile may help decipher its roles under specific conditions. Here we present the X-ray structures of human galectin-4 N-terminal CRD (galectin-4N) bound to different saccharide ligands. Galectin-4's overall fold and its core interactions to lactose are similar to other galectin CRDs. Galectin-4N recognises the sulfate cap of 3'-sulfated glycans by a weak interaction through Arg45 and two water-mediated hydrogen bonds via Trp84 and Asn49. When galectin-4N interacts with the H-antigen mimic, 2'-fucosyllactose, an interaction is formed between the ring oxygen of fucose and Arg45. The extended binding site of galectin-4N may not be well suited to the A/B-antigen determinants, α-GalNAc/α-Gal, specifically due to clashes with residue Phe47. Overall, galectin-4N favours sulfated glycans whilst galectin-4C prefers blood group determinants. However, the two CRDs of galectin-4 can, to a less extent, recognise each other's ligands.
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Affiliation(s)
- Khuchtumur Bum-Erdene
- Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia
| | - Hakon Leffler
- Section MIG, Department of Laboratory Medicine, Lund University, BMC-C1228b, Klinikgatan 28, SE-22184 Lund, Sweden
| | - Ulf J. Nilsson
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, PO Box 124, SE-22100 Lund, Sweden
| | - Helen Blanchard
- Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia
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