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1
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Liu H, Li Z, Xu X, Xu B, Li Z. Network pharmacology and in vitro analyses reveal EGCG inhibits breast cancer progression via suppression of the EGFR/Src pathway. Biochem Biophys Res Commun 2025; 769:151942. [PMID: 40359763 DOI: 10.1016/j.bbrc.2025.151942] [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: 02/17/2025] [Revised: 04/08/2025] [Accepted: 05/04/2025] [Indexed: 05/15/2025]
Abstract
Breast cancer (BRCA) has emerged as a significant threat to women's health. Epigallocatechin gallate (EGCG) has shown promising therapeutic potential. However, its mechanisms of action are not yet fully understood. This study employed a network pharmacology (NP) approach to investigate the key targets and signaling pathways regulated by EGCG in BRCA, and validated the findings through cell experiments. Our comprehensive analysis identified 10 key targets of EGCG, suggesting that EGCG may inhibit the EGFR/Src pathway. Consistently, our cell experiments revealed that EGCG could significantly inhibit the migration, invasion, and proliferation of BRCA cells. Furthermore, EGCG downregulated the protein levels of EGFR, Src, PI3K, Akt, STAT3, and Bcl2. These experimental findings support the results of the NP analysis. In conclusion, our NP and in vitro studies indicate that EGCG inhibits BRCA progression by suppressing the EGFR/Src pathway and its downstream signals transduction including the PI3K/Akt and STAT3/Bcl2 pathways.
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Affiliation(s)
- Huiying Liu
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Zhiqiang Li
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
| | - Xiaohui Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Shandong, 266000, China
| | - Binwu Xu
- The Institute of Translational Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Jiangxi Province Key Laboratory of Precision Cell Therapy, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Rehabilitation Medicine, The Department of Rehabilitation Medicine, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
| | - Zhipeng Li
- State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang, 330047, China.
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2
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Han JH, Heo JB, Lee HW, Park MH, Choi J, Yun EJ, Lee S, Song GY, Myung CS. Novel carbazole attenuates vascular remodeling through STAT3/CIAPIN1 signaling in vascular smooth muscle cells. Acta Pharm Sin B 2025; 15:1463-1479. [PMID: 40370537 PMCID: PMC12069901 DOI: 10.1016/j.apsb.2024.12.035] [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: 07/19/2024] [Revised: 09/24/2024] [Accepted: 10/22/2024] [Indexed: 05/16/2025] Open
Abstract
This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells (VSMCs), which play a crucial role in vascular remodeling using 9H-Carbazol-3-yl 4-aminobenzoate (CAB). CAB significantly attenuated platelet-derived growth factor (PDGF)-induced VSMC proliferation and migration. CAB suppressed PDGF-induced STAT3 activation by directly binding to the SH2 domain of STAT3. Downregulation of STAT3 phosphorylation by CAB attenuated CIAPIN1/JAK2/STAT3 axis through a decrease in CIAPIN1 transcription. Furthermore, abrogated CIAPIN1 decreased KLF4-mediated VSMC dedifferentiation and increased CDKN1B-induced cell cycle arrest and MMP9 suppression. CAB inhibited intimal hyperplasia in injury-induced neointima animal models by inhibition of the CIAPIN1/JAK2/STAT3 axis. However, CIAPIN1 overexpression attenuated CAB-mediated suppression of VSMC proliferation, migration, phenotypic switching, and intimal hyperplasia. Our study clarified the molecular mechanism underlying STAT3 inhibition of VSMC phenotypic switching and vascular remodeling and identified novel active CAB. These findings demonstrated that STAT3 can be a major regulator to control CIAPIN1/JAK2/STAT3 axis that may be a therapeutic target for treating vascular proliferative diseases.
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Affiliation(s)
- Joo-Hui Han
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Woosuk University, Wanju 55338, Republic of Korea
| | - Jong-Beom Heo
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Hyung-Won Lee
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Min-Ho Park
- Institute of Drug Research and Development, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Jangmi Choi
- Institute of Drug Research and Development, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Eun Joo Yun
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Seongpyo Lee
- College of Pharmacy, Woosuk University, Wanju 55338, Republic of Korea
| | - Gyu Yong Song
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Chang-Seon Myung
- Department of Pharmacology, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
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3
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Liu BHM, Lin Y, Long X, Hung SW, Gaponova A, Ren F, Zhavoronkov A, Pun FW, Wang CC. Utilizing AI for the Identification and Validation of Novel Therapeutic Targets and Repurposed Drugs for Endometriosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2406565. [PMID: 39666559 PMCID: PMC11792045 DOI: 10.1002/advs.202406565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/08/2024] [Indexed: 12/14/2024]
Abstract
Endometriosis affects over 190 million women globally, and effective therapies are urgently needed to address the burden of endometriosis on women's health. Using an artificial intelligence (AI)-driven target discovery platform, two unreported therapeutic targets, guanylate-binding protein 2 (GBP2) and hematopoietic cell kinase (HCK) are identified, along with a drug repurposing target, integrin beta 2 (ITGB2) for the treatment of endometriosis. GBP2, HCK, and ITGB2 are upregulated in human endometriotic specimens. siRNA-mediated knockdown of GBP2 and HCK significantly reduced cell viability and proliferation while stimulating apoptosis in endometrial stromal cells. In subcutaneous and intraperitoneal endometriosis mouse models, siRNAs targeting GBP2 and HCK notably reduced lesion volume and weight, with decreased proliferation and increased apoptosis within lesions. Both subcutaneous and intraperitoneal administration of Lifitegrast, an approved ITGB2 antagonist, effectively suppresses lesion growth. Collectively, these data present Lifitegrast as a previously unappreciated intervention for endometriosis treatment and identify GBP2 and HCK as novel druggable targets in endometriosis treatment. This study underscores AI's potential to accelerate the discovery of novel drug targets and facilitate the repurposing of treatment modalities for endometriosis.
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Affiliation(s)
- Bonnie Hei Man Liu
- Insilico Medicine Hong Kong Ltd.Unit 310, 3/F, Building 8W, Hong Kong Science and Technology ParkHong KongChina
| | - Yuezhen Lin
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong KongChina
| | - Xi Long
- Insilico Medicine Hong Kong Ltd.Unit 310, 3/F, Building 8W, Hong Kong Science and Technology ParkHong KongChina
| | - Sze Wan Hung
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong KongChina
| | - Anna Gaponova
- Insilico Medicine Hong Kong Ltd.Unit 310, 3/F, Building 8W, Hong Kong Science and Technology ParkHong KongChina
| | - Feng Ren
- Insilico Medicine Shanghai Ltd.9F, Chamtime Plaza Block C, Lane 2889, Jinke Road, Pudong New AreaShanghai201203China
| | - Alex Zhavoronkov
- Insilico Medicine Hong Kong Ltd.Unit 310, 3/F, Building 8W, Hong Kong Science and Technology ParkHong KongChina
- Buck Institute for Research on Aging8001 Redwood Blvd.NovatoCA94945USA
| | - Frank W. Pun
- Insilico Medicine Hong Kong Ltd.Unit 310, 3/F, Building 8W, Hong Kong Science and Technology ParkHong KongChina
| | - Chi Chiu Wang
- Department of Obstetrics and GynaecologyThe Chinese University of Hong KongHong KongChina
- Reproduction and DevelopmentLi Ka Shing Institute of Health SciencesThe Chinese University of Hong KongHong KongChina
- School of Biomedical SciencesThe Chinese University of Hong KongHong KongChina
- Chinese University of Hong Kong‐Sichuan University Joint Laboratory in Reproductive MedicineThe Chinese University of Hong KongHong KongChina
- State Key Laboratory of Chinese Medicine ModernizationInnovation Center of Yangtze River Delta Zhejiang UniversityJiaxing314102China
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4
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Selzer AM, Gerlach G, Gonzalez-Areizaga G, Wales TE, Cui SY, Iyer P, Engen JR, Camacho C, Ishima R, Smithgall TE. An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck. J Biol Chem 2025; 301:108088. [PMID: 39675702 PMCID: PMC11786751 DOI: 10.1016/j.jbc.2024.108088] [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: 08/24/2024] [Revised: 11/15/2024] [Accepted: 12/10/2024] [Indexed: 12/17/2024] Open
Abstract
While ATP-site inhibitors for protein-tyrosine kinases are often effective drugs, their clinical utility can be limited by off-target activity and acquired resistance mutations due to the conserved nature of the ATP-binding site. However, combining ATP-site and allosteric kinase inhibitors can overcome these shortcomings in a double-drugging framework. Here we explored the allosteric effects of two pyrimidine diamines, PDA1 and PDA2, on the conformational dynamics and activity of the Src-family tyrosine kinase Hck, a promising drug target for acute myeloid leukemia. Using 1H-15N HSQC NMR, we mapped the binding site for both analogs to the SH3 domain. Despite the shared binding site, PDA1 and PDA2 had opposing effects on near-full-length Hck dynamics by hydrogen-deuterium exchange mass spectrometry, with PDA1 stabilizing and PDA2 disrupting the overall kinase conformation. Kinase activity assays were consistent with these observations, with PDA2 enhancing kinase activity while PDA1 was without effect. Molecular dynamics simulations predicted selective bridging of the kinase domain N-lobe and SH3 domain by PDA1, a mechanism of allosteric stabilization supported by site-directed mutagenesis of N-lobe contact sites. Cellular thermal shift assays confirmed SH3 domain-dependent interaction of PDA1 with WT Hck in myeloid leukemia cells and with a kinase domain gatekeeper mutant (T338M). These results identify PDA1 as a starting point for Src-family kinase allosteric inhibitor development that may work in concert with ATP-site inhibitors to suppress the evolution of resistance.
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Affiliation(s)
- Ari M Selzer
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Gabriella Gerlach
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Giancarlo Gonzalez-Areizaga
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Thomas E Wales
- Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, Massachusetts, USA
| | - Stephanie Y Cui
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA
| | - Prema Iyer
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania, USA
| | - John R Engen
- Department of Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, Massachusetts, USA
| | - Carlos Camacho
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Rieko Ishima
- Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Thomas E Smithgall
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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5
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Selzer AM, Alvarado JJ, Smithgall TE. Cocrystallization of the Src-Family Kinase Hck with the ATP-Site Inhibitor A-419259 Stabilizes an Extended Activation Loop Conformation. Biochemistry 2024; 63:2594-2601. [PMID: 39315638 PMCID: PMC11483750 DOI: 10.1021/acs.biochem.4c00323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/29/2024] [Accepted: 09/13/2024] [Indexed: 09/25/2024]
Abstract
Hematopoietic cell kinase (Hck) is a member of the Src kinase family and is a promising drug target in myeloid leukemias. Here, we report the crystal structure of human Hck in complex with the pyrrolopyrimidine inhibitor A-419259, determined at a resolution of 1.8 Å. This structure reveals the complete Hck active site in the presence of A-419259, including the αC-helix, the DFG motif, and the activation loop. A-419259 binds at the ATP-site of Hck and induces an overall closed conformation of the kinase with the regulatory SH3 and SH2 domains bound intramolecularly to their respective internal ligands. A-419259 stabilizes the DFG-in/αC-helix-out conformation observed previously with Hck and the pyrazolopyrimidine inhibitor PP1 (PDB: 1QCF). However, the activation loop conformations are distinct, with PP1 inducing a folded loop structure with the tyrosine autophosphorylation site (Tyr416) pointing into the ATP binding site, while A-419259 stabilizes an extended loop conformation with Tyr416 facing out into the solvent. Autophosphorylation also induces activation loop extension and significantly reduces the Hck sensitivity to PP1 but not A-419259. In cancer cells where Hck is constitutively active, the extended autophosphorylation loop may render Hck more sensitive to inhibitors like A-419259 which prefer this kinase conformation. More generally, these results provide additional insight into targeted kinase inhibitor design and how conformational preferences of inhibitors may impact selectivity and potency.
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Affiliation(s)
- Ari M. Selzer
- Department of Microbiology
and Molecular Genetics, University of Pittsburgh
School of Medicine, 450 Technology Drive, Pittsburgh, Pennsylvania PA 15219, United States
| | - John J. Alvarado
- Department of Microbiology
and Molecular Genetics, University of Pittsburgh
School of Medicine, 450 Technology Drive, Pittsburgh, Pennsylvania PA 15219, United States
| | - Thomas E. Smithgall
- Department of Microbiology
and Molecular Genetics, University of Pittsburgh
School of Medicine, 450 Technology Drive, Pittsburgh, Pennsylvania PA 15219, United States
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6
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Hayashi SY, Craddock BP, Miller WT. Effects of heterologous kinase domains on growth factor receptor specificity. Cell Signal 2024; 122:111307. [PMID: 39048037 PMCID: PMC11707674 DOI: 10.1016/j.cellsig.2024.111307] [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: 04/18/2024] [Revised: 07/02/2024] [Accepted: 07/19/2024] [Indexed: 07/27/2024]
Abstract
The kinase domains of receptor tyrosine kinases (RTKs) are highly conserved, yet they are able to discriminate among potential substrates to selectively activate downstream signaling pathways. In this study, we tested the importance of catalytic domain specificity by creating two series of chimeric RTKs. In one set, the kinase domain of insulin-like growth factor I receptor (IGF1R) was replaced by the kinase domains from insulin receptor (IR), macrophage stimulating protein 1 receptor/Ron (Ron) or Src. In the other set of chimeras, the kinase domain of epidermal growth factor receptor (EGFR) was similarly replaced by the kinase domains of IR, Ron, or Src. We expressed the wild-type and chimeric forms of the receptors in mammalian cells. For some signaling events, such as recognition of IRS1, the identity of the tyrosine kinase catalytic domain did not appear to be crucial. In contrast, recognition of some sites, such as the C-terminal autophosphorylation sites on EGFR, did depend on the identity of the kinase domain. Our data also showed that ligand dependence was lost when the native kinase domains were replaced by Src, suggesting that the identity of the kinase domains could be important for proper receptor regulation. Overall, the results are consistent with the idea that the fidelity of RTK signaling depends on co-localization and targeting with substrates, as well as on the intrinsic specificity of the kinase domain.
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Affiliation(s)
- Samantha Y Hayashi
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA 11794
| | - Barbara P Craddock
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA 11794
| | - W Todd Miller
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA 11794; Department of Veterans Affairs Medical Center, Northport, NY 11768, USA.
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7
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Marugán C, Sanz‐Gómez N, Ortigosa B, Monfort‐Vengut A, Bertinetti C, Teijo A, González M, Alonso de la Vega A, Lallena MJ, Moreno‐Bueno G, de Cárcer G. TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling. Mol Oncol 2024; 18:1531-1551. [PMID: 38357786 PMCID: PMC11161735 DOI: 10.1002/1878-0261.13602] [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: 09/11/2023] [Revised: 01/03/2024] [Accepted: 01/26/2024] [Indexed: 02/16/2024] Open
Abstract
Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.
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Grants
- 2018-20I114 Spanish National Research Council (CSIC)
- 2021-AEP035 Spanish National Research Council (CSIC)
- 2022-20I018 Spanish National Research Council (CSIC)
- FJC2020-044620-I Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2019-104644RB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2021-125705OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- PID2022-136854OB-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- RTI2018-095496-B-I00 Ministerio de Ciencia, Innovación, Agencia Estatal de Investigación MCIN/AEI/FEDER
- CB16/12/00295 Instituto de Salud Carlos III - CIBERONC
- LABAE16017DECA Spanish Association Against Cancer (AECC) Scientific Foundation
- POSTD234371SANZ Spanish Association Against Cancer (AECC) Scientific Foundation
- PROYE19036MOR Spanish Association Against Cancer (AECC) Scientific Foundation
- Spanish National Research Council (CSIC)
- Spanish Association Against Cancer (AECC) Scientific Foundation
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Affiliation(s)
- Carlos Marugán
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Natalia Sanz‐Gómez
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Beatriz Ortigosa
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Monfort‐Vengut
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Cristina Bertinetti
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Ana Teijo
- Pathology DepartmentMD Anderson Cancer CenterMadridSpain
| | - Marta González
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - Alicia Alonso de la Vega
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
| | - María José Lallena
- Discovery Chemistry Research and TechnologyEli Lilly and CompanyMadridSpain
| | - Gema Moreno‐Bueno
- Translational Cancer Research Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Alberto Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- MD Anderson International FoundationMadridSpain
- Biomedical Cancer Research Network (CIBERONC)MadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
| | - Guillermo de Cárcer
- Cell Cycle & Cancer Biomarkers Laboratory, Cancer DepartmentInstituto de Investigaciones Biomédicas Sols‐Morreale (IIBM) CSIC‐UAMMadridSpain
- CSIC Conexión‐Cáncer Hub (https://conexion‐cancer.csic.es)
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8
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Deng RR, Yuan YP. Ropivacaine inhibits the proliferation and metastasis of gastric cancer cells via the SNX10/SRC/STAT3 pathway. Chem Biol Drug Des 2024; 103:e14405. [PMID: 37989501 DOI: 10.1111/cbdd.14405] [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: 07/24/2023] [Revised: 10/13/2023] [Accepted: 11/09/2023] [Indexed: 11/23/2023]
Abstract
Gastric cancer currently has no effective treatment due to its high metastasis and heterogeneity. It has been reported that ropivacaine (Rop) can inhibit the growth, migration, and invasion of gastric cancer. However, the therapeutic mechanism of Rop still needs to be further explored to provide insights for its clinical application. This study aimed to explore the effects of Rop on the growth, migration, and invasion of gastric cancer cells and the underlying mechanisms. The expression levels of SNX10 were assessed in gastric cancer tissues and cell line AGS by qRT-PCR. Cell Counting Kit-8 (CCK8) assay, wound-healing assay, and transwell assay were then used to examine the effects of Rop on the AGS cell viability, migration, invasion, and proliferation, respectively. Additionally, colony formation assay was used to measure cell proliferation ability, and flow cytometry was used to detect apoptosis level. Protein levels of SNX10, SRC, and STAT3 were detected by western blot. According to the experimental results, the decreased SNX10 mRNA expression was observed in gastric cancer tissue and cell line AGS. Rop inhibited the proliferation, migration, and invasion of AGS cells, but promoted apoptosis and upregulated SNX10 expression. Moreover, Rop inhibited the expression of MMP-2 and MMP-9, phosphorylation of SRC and STAT3. SNX10 knockdown could reverse Rop-induced anticancer effects. Collectively, Rop showed a potential role in preventing proliferation and metastasis of gastric cancer. The action mechanism of Rop may be related to the upregulation of SNX10 expression and further inhibition of SRC/STAT3 signaling pathway. Our findings provide new insights into the anticancer properties of Rop.
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Affiliation(s)
- Rong-Rong Deng
- Department of Anaesthesiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of Anaesthesiology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
| | - You-Ping Yuan
- Department of Anaesthesiology, Wujin Hospital Affiliated with Jiangsu University, Changzhou, China
- Department of Anaesthesiology, The Wujin Clinical College of Xuzhou Medical University, Changzhou, China
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9
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Li N, Lin G, Zhang H, Sun J, Gui M, Liu Y, Li W, Zhan Z, Li Y, Pan S, Liu J, Tang J. Lyn attenuates sepsis-associated acute kidney injury by inhibition of phospho-STAT3 and apoptosis. Biochem Pharmacol 2023; 211:115523. [PMID: 37003346 DOI: 10.1016/j.bcp.2023.115523] [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: 12/20/2022] [Revised: 03/22/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023]
Abstract
Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening condition associated with high mortality and morbidity. However, the underlying pathogenesis of SA-AKI is still unclear. Lyn belongs to Src family kinases (SFKs), which exert numerous biological functions including modulation in receptor-mediated intracellular signaling and intercellular communication. Previous studies demonstrated that Lyn gene deletion obviously aggravates LPS-induced lung inflammation, but the role and possible mechanism of Lyn in SA-AKI have not been reported yet. Here, we found that Lyn protected against renal tubular injury in cecal ligation and puncture (CLP) induced AKI mouse model by inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation and cell apoptosis. Moreover, Lyn agonist MLR-1023 pretreatment improved renal function, inhibited STAT3 phosphorylation and decreased cell apoptosis. Thus, Lyn appears to play a crucial role in orchestrating STAT3-mediated inflammation and cell apoptosis in SA-AKI. Hence, Lyn kinase may be a promising therapeutic target for SA-AKI.
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Affiliation(s)
- Nannan Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Guoxin Lin
- Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Jian Sun
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Ming Gui
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Yan Liu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Wei Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Zishun Zhan
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Yisu Li
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Shiqi Pan
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Jishi Liu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Juan Tang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
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10
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STAT3 and PD-L1 are negatively correlated with ATM and have impact on the prognosis of triple-negative breast cancer patients with low ATM expression. Breast Cancer Res Treat 2022; 196:45-56. [PMID: 36056297 DOI: 10.1007/s10549-022-06679-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/04/2022] [Indexed: 11/02/2022]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is known for its aggressive behaviors and lacking of effective treatment. Programmed cell death ligand-1 (PD-L1) inhibitor has just been approved for using in the management of advanced TNBC. To accurately screen TNBC sensitive to anti-PD-L1 treatment and to explore the feasibility of the ataxia-telangiectasia mutation protein (ATM) inhibitor combined with PD-L1 inhibitor, radiotherapy and chemotherapy, we focus on whether ATM participates in the regulation of PD-L1 and affects the prognosis of patients through c-Src, signal transducer and activator of transcription 1&3 (STAT1 and STAT3). MATERIALS AND METHODS We used immunohistochemical staining to explore the relationship of ATM with c-Src, STAT1, STAT3, PD-1/PD-L1, Tumor-infiltrating lymphocytes (TILs), as well as other clinicopathologic features in 86 pathological stage III TNBCs. Their impact on prognosis was also explored. RESULTS We found ATM expression was negatively correlated with STAT1, STAT3, PD-L1, TILs and CD8 + cells in TNBC. STAT1 positively correlated the expression of PD-L1. In TNBC with ATM low expression, STAT3 was an independent factor for improved prognosis, while PD-L1 was an independent negative prognostic factor. Furthermore, in low ATM group, the phosphorylation of tyrosine at position 419 of c-Src (p-c-src Y419) was correlated with the overexpression of STAT3. CONCLUSION Locally advanced TNBC with low ATM expression may be more likely to benefit from anti-PD-L1 inhibitors. The feasibility of ATM functional inhibitor combined with immune checkpoint blockade therapies in the treatment of TNBC is also worthy of further exploration. Our study suggests that STAT3 has different impacts on tumor progression in different tumors.
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11
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Miller KJ, Asim M. Unravelling the Role of Kinases That Underpin Androgen Signalling in Prostate Cancer. Cells 2022; 11:cells11060952. [PMID: 35326402 PMCID: PMC8946764 DOI: 10.3390/cells11060952] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023] Open
Abstract
The androgen receptor (AR) signalling pathway is the key driver in most prostate cancers (PCa), and is underpinned by several kinases both upstream and downstream of the AR. Many popular therapies for PCa that target the AR directly, however, have been circumvented by AR mutation, such as androgen receptor variants. Some upstream kinases promote AR signalling, including those which phosphorylate the AR and others that are AR-regulated, and androgen regulated kinase that can also form feed-forward activation circuits to promotes AR function. All of these kinases represent potentially druggable targets for PCa. There has generally been a divide in reviews reporting on pathways upstream of the AR and those reporting on AR-regulated genes despite the overlap that constitutes the promotion of AR signalling and PCa progression. In this review, we aim to elucidate which kinases—both upstream and AR-regulated—may be therapeutic targets and require future investigation and ongoing trials in developing kinase inhibitors for PCa.
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12
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Kim B, Lee K, Park B. Minecoside promotes apoptotic progression through STAT3 inactivation in breast cancer cells. Oncol Lett 2022; 23:94. [PMID: 35154425 PMCID: PMC8822415 DOI: 10.3892/ol.2022.13214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 01/04/2022] [Indexed: 11/30/2022] Open
Abstract
Breast cancer is one of the most common malignant tumors in women worldwide, and is a major cause of mortality and morbidity in cancer patients. Constitutive activation of STAT3 has been found in a variety of malignant tumors, including breast cancer. Since STAT3 activation is capable of regulating various important features of tumor cells, identification of a novel STAT3 inhibitor is considered a potential strategy for treating breast cancer. The aim of the present study was to examine whether minecoside (MIN), an active compound extracted from Veronica peregrina L., exerts an antitumor effect by inhibiting STAT3 signaling pathway in MDA-MB-231 cells. The results revealed that MIN inhibited the constitutive STAT3 activation in a dose- and time-dependent manner. MIN also blocked the nuclear translocation of STAT3 and suppressed STAT3-DNA binding. In addition, MIN downregulated the STAT3-mediated expression of proteins such as Bcl-xL, Bcl-2, CXCR4, VEGF, and cyclin D1. Subsequently, MIN promoted the caspase-dependent apoptosis in MDA-MB-231 cells. Overall, results of the present study provide evidence that MIN exerted anticancer activity via inhibition of the STAT3 signaling pathway. Further studies using animal models are required to determine the potential of this molecule as an anticancer drug.
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Affiliation(s)
- Buyun Kim
- College of Pharmacy, Keimyung University, Dalseo‑Gu, Daegu, North Gyeongsang 704‑701, Republic of Korea
| | - Ki Lee
- College of Pharmacy, Korea University, Sejong 339‑770, Republic of Korea
| | - Byoungduck Park
- College of Pharmacy, Keimyung University, Dalseo‑Gu, Daegu, North Gyeongsang 704‑701, Republic of Korea
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13
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Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1α and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact 2021; 351:109729. [PMID: 34717917 DOI: 10.1016/j.cbi.2021.109729] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022]
Abstract
Colon cancer patients with mutant KRAS are resistant to cetuximab, an antibody directed against the epidermal growth factor receptor. New treatment options are needed to improve survival in patients with KRAS mutated colorectal cancer. Digitoxin is a cardiotonic drug, which has been demonstrated to exhibit anticancer effects in a number of cancers. However, the anticancer mechanisms of digitoxin in KRAS mutant human colon cancer cells remain elusive. Our result demonstrated that digitoxin but not cetuximab markedly decreased the expression of hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3) and p-STAT3 protein in KRAS mutant colon cancer cells. Further analysis revealed that digitoxin inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. The phosphorylation levels of ribosomal protein S6 kinase (p70S6K) and eIF4E binding protein-1 (4E-BP1) were significantly suppressed by digitoxin. Digitoxin inhibited the expression and activation of STAT3 through upregulation of phosphatase and tensin homolog deleted on chromosome ten (PTEN), SHP1 and protein inhibitors of activated STAT3 (PIAS3) and direct binding to STAT3. Meanwhile, digitoxin inhibited HIF-1α in STAT3-independent manner in KRAS mutant colon cancer cells. Moreover, digitoxin promoted apoptosis and inhibited proliferation and migration, which was potentially mediated by suppression of HIF-1α and STAT3. We also found that digitoxin administration inhibited tumor growth in a mouse xenograft model. Taken together, our findings highlight the therapeutic potential of digitoxin for the treatment of cetuximab-resistant human colon cancer.
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14
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Giordano M, Decio A, Battistini C, Baronio M, Bianchi F, Villa A, Bertalot G, Freddi S, Lupia M, Jodice MG, Ubezio P, Colombo N, Giavazzi R, Cavallaro U. L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:319. [PMID: 34645505 PMCID: PMC8513260 DOI: 10.1186/s13046-021-02117-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/26/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. METHODS The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. RESULTS We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. CONCLUSIONS Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.
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Affiliation(s)
- Marco Giordano
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy
| | - Alessandra Decio
- Laboratory of Tumor Metastasis Therapeutics, Mario Negri Institute for Pharmacological Research - IRCCS, Milan, Italy
| | - Chiara Battistini
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy
| | - Micol Baronio
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy
| | - Fabrizio Bianchi
- Cancer Biomarkers Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy
| | - Alessandra Villa
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy.,Philochem AG, Otelfingen, Switzerland
| | - Giovanni Bertalot
- Department of Experimental Oncology, European Institute of Oncology IRCSS, Milan, Italy.,Division of Anatomical Pathology, Santa Chiara Hospital, Trento, Italy
| | - Stefano Freddi
- Department of Experimental Oncology, European Institute of Oncology IRCSS, Milan, Italy
| | - Michela Lupia
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy
| | - Maria Giovanna Jodice
- Department of Experimental Oncology, European Institute of Oncology IRCSS, Milan, Italy
| | - Paolo Ubezio
- Laboratory of Tumor Metastasis Therapeutics, Mario Negri Institute for Pharmacological Research - IRCCS, Milan, Italy
| | - Nicoletta Colombo
- Division of Gynecologic Oncology, European Institute of Oncology IRCSS, Milan, Italy.,University of Milan-Bicocca, Milan, Italy
| | - Raffaella Giavazzi
- Laboratory of Tumor Metastasis Therapeutics, Mario Negri Institute for Pharmacological Research - IRCCS, Milan, Italy
| | - Ugo Cavallaro
- Unit of Gynaecological Oncology Research, European Institute of Oncology IRCSS, Milan, Italy.
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15
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Kurahara LH, Hiraishi K, Yamamura A, Zhang Y, Abe K, Yahiro E, Aoki M, Koga K, Yokomise H, Go T, Ishikawa K, Bo Z, Kishi H, Kobayashi S, Aoki-Shoi N, Toru S, Inoue R, Hirano K. Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn. J Mol Cell Cardiol 2020; 148:50-62. [PMID: 32889002 DOI: 10.1016/j.yjmcc.2020.08.013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/03/2020] [Accepted: 08/18/2020] [Indexed: 12/26/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-β2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.
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Affiliation(s)
- Lin Hai Kurahara
- Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan; Department of Physiology, Fukuoka University School of Medicine, Fukuoka, Japan.
| | - Keizo Hiraishi
- Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan; Department of Physiology, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Aya Yamamura
- Department of Physiology, Aichi Medical University, Nagakute, Japan
| | - Ying Zhang
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Minami-Kogushi, Ube, Yamaguchi, Japan
| | - Kohtaro Abe
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Eiji Yahiro
- Fukuoka University Medical Education Center, Fukuoka University School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Mikiko Aoki
- Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Kaori Koga
- Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hiroyasu Yokomise
- Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan
| | - Tetsuhiko Go
- Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan
| | - Kaori Ishikawa
- Department of General Medicine, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan
| | - Zhang Bo
- Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hiroko Kishi
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Minami-Kogushi, Ube, Yamaguchi, Japan
| | - Sei Kobayashi
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Yamaguchi University, Minami-Kogushi, Ube, Yamaguchi, Japan
| | - Narumi Aoki-Shoi
- Department of Chemistry, Faculty of Science, Fukuoka University, Fukuoka, Japan
| | - Satoh Toru
- Division of Cardiology, Department of Medicine, Kyorin University School of Medicine, Tokyo, Japan
| | - Ryuji Inoue
- Department of Physiology, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Katsuya Hirano
- Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kita-gun, Miki-cho, Kagawa, Japan
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16
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Zuo HX, Jin Y, Wang Z, Li MY, Zhang ZH, Wang JY, Xing Y, Ri MH, Jin CH, Xu GH, Piao LX, Ma J, Jin X. Curcumol inhibits the expression of programmed cell death-ligand 1 through crosstalk between hypoxia-inducible factor-1α and STAT3 (T705) signaling pathways in hepatic cancer. JOURNAL OF ETHNOPHARMACOLOGY 2020; 257:112835. [PMID: 32278762 DOI: 10.1016/j.jep.2020.112835] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/16/2020] [Accepted: 04/01/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Curcuma wenyujin is a Chinese traditional herbal medicine that is commonly used as an anti-oxidant, anti-proliferative, and anti-tumorigenic agent. Curcumol is a representative index component for the quality control of the essential oil of Curcuma wenyujin, which is currently used as an anti-cancer drug, and is included in the State Pharmacopoeia Commission of the People's Republic of China (2005). However, the mechanisms of action and molecular functions of curcumol are not yet fully elucidated. AIM OF THE STUDY This study aimed to identify new effects of curcumol from the perspective of cancer immunotherapy. MATERIALS AND METHODS The underlying mechanism of the inhibition of programmed cell death-ligand 1 (PD-L1) activation by curcumol was investigated in vitro via homology modeling, molecular docking experiments, luciferase reporter assays, MTT assays, RT-PCR, western blotting, and immunofluorescence assays. Changes in cellular proliferation, angiogenesis, and the tumor-killing activity of T-cells were analyzed via EdU labeling, colony formation, flow cytometry, wound-healing, Matrigel Transwell invasion, tube formation, and T-cell killing. The anti-tumor activity of curcumol was assessed in vivo in a murine xenograft model using Hep3B cells. RESULTS Curcumol reduced the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) via JAK1, JAK2, and Src pathways and inhibited hypoxia-inducible factor-1α (HIF-1α) protein synthesis via mTOR/p70S6K/eIF4E and MAPK pathways. Furthermore, we revealed crosstalk between STAT3 and HIF-1α pathways, which collaboratively regulated PD-L1 activation, and that curcumol played a role in this regulation. Curcumol inhibited cell proliferation, S-phase progression, tube formation, invasion, and metastasis by inhibiting PD-L1. In addition, curcumol restored the activity of cytotoxic T-cells and their capacity for tumor cell killing by inhibiting PD-L1. In vivo experiments confirmed that curcumol inhibited tumor growth in a xenograft model. CONCLUSIONS These results illustrated that curcumol inhibits the expression of PD-L1 through crosstalk between HIF-1α and p-STAT3 (T705) signaling pathways in hepatic cancer. Thus, curcumol might represent a promising lead compound for the development of new targeted anti-cancer therapeutics.
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Affiliation(s)
- Hong Xiang Zuo
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China; College of Pharmacy, Beihua University, Jilin, 132013, Jilin Province, China
| | - Yong Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhe Wang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Ming Yue Li
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhi Hong Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Jing Ying Wang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Yue Xing
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Myong Hak Ri
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Cheng Hua Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Guang Hua Xu
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Lian Xun Piao
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Juan Ma
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
| | - Xuejun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
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17
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Tang L, Long J, Li K, Zhang X, Chen X, Peng C. A novel chalcone derivative suppresses melanoma cell growth through targeting Fyn/Stat3 pathway. Cancer Cell Int 2020; 20:256. [PMID: 32565740 PMCID: PMC7302361 DOI: 10.1186/s12935-020-01336-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 06/09/2020] [Indexed: 12/14/2022] Open
Abstract
Background Fyn has been documented to have oncogenic features in multiple tumors, which might be a potential therapeutic target, however, few studies on the function role of Fyn and its specific inhibitors in melanoma. Methods We investigated the impacts of Fyn and its inhibitor Lj-1-60 on melanoma through bioinformatics analysis, western blot, cell viability, cell cycle and apoptosis and xenograft tumor model as well as immunohistochemical staining. Pull-down and in vitro kinase assay were used to demonstrate Lj-1-60 targeting Fyn. Transcriptome sequencing and RT-PCR were adopted to confirm the potential mechanisms of Lj-1-60 in melanoma. Results Our findings showed that Fyn was overexpressed in melanoma cells and knocked down of Fyn suppressed the proliferation of melanoma cells. To identify the potential inhibitors of Fyn, our in-house library including total of 111,277 chemicals was conducted to vitro screening, among those compounds, 83 inhibitors were further detected to explore the effect on melanoma cells growth and discovered a novel chalcone derivative Lj-1-60 that exhibited low cellular toxicity and high anti-tumor efficacy. Lj-1-60 directly was associated with Fyn and inhibited the Fyn kinase activity with Stat3 as substrate. What's more, Lj-1-60 suppressed the proliferation of melanoma in vitro and in vivo through inducing cell cycle arrest and apoptosis. Moreover, the activation of Stat3 had also been abrogated both in Lj-1-60 treated melanoma cells or Fyn knocked down cells. Conclusion Our study revealed a novel Fyn inhibitor that could significantly suppress melanoma growth, which is a promising potential inhibitor for melanoma treatment.
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Affiliation(s)
- Ling Tang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan China.,Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Jing Long
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Keke Li
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Xu Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China
| | - Cong Peng
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410000 Hunan China.,Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan China.,Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan China
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18
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Parri E, Kuusanmäki H, van Adrichem AJ, Kaustio M, Wennerberg K. Identification of novel regulators of STAT3 activity. PLoS One 2020; 15:e0230819. [PMID: 32231398 PMCID: PMC7108870 DOI: 10.1371/journal.pone.0230819] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/09/2020] [Indexed: 01/05/2023] Open
Abstract
STAT3 mediates signalling downstream of cytokine and growth factor receptors where it acts as a transcription factor for its target genes, including oncogenes and cell survival regulating genes. STAT3 has been found to be persistently activated in many types of cancers, primarily through its tyrosine phosphorylation (Y705). Here, we show that constitutive STAT3 activation protects cells from cytotoxic drug responses of several drug classes. To find novel and potentially targetable STAT3 regulators we performed a kinase and phosphatase siRNA screen with cells expressing either a hyperactive STAT3 mutant or IL6-induced wild type STAT3. The screen identified cell division cycle 7-related protein kinase (CDC7), casein kinase 2, alpha 1 (CSNK2), discoidin domain-containing receptor 2 (DDR2), cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 4-kinase 2-alpha (PI4KII), C-terminal Src kinase (CSK) and receptor-type tyrosine-protein phosphatase H (PTPRH) as potential STAT3 regulators. Using small molecule inhibitors targeting these proteins, we confirmed dose and time dependent inhibition of STAT3-mediated transcription, suggesting that inhibition of these kinases may provide strategies for dampening STAT3 activity in cancers.
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Affiliation(s)
- Elina Parri
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Heikki Kuusanmäki
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- Biotech Research & Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark
| | | | - Meri Kaustio
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Krister Wennerberg
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- Biotech Research & Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark
- * E-mail:
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19
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Hu YS, Han X, Liu XH. STAT3: A Potential Drug Target for Tumor and Inflammation. Curr Top Med Chem 2019; 19:1305-1317. [PMID: 31218960 DOI: 10.2174/1568026619666190620145052] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/25/2019] [Accepted: 05/09/2019] [Indexed: 12/12/2022]
Abstract
STAT (Signal Transducers and Activators of Transcription) is a cellular signal transcription factor involved in the regulation of many cellular activities, such as cell differentiation, proliferation, angiogenesis in normal cells. During the study of the STAT family, STAT3 was found to be involved in many diseases, such as high expression and sustained activation of STAT3 in tumor cells, promoting tumor growth and proliferation. In the study of inflammation, it was found that it plays an important role in the anti-inflammatory and repairing of damage tissues. Because of the important role of STAT3, a large number of studies have been obtained. At the same time, after more than 20 years of development, STAT3 has also been used as a target for drug therapy. And the discovery of small molecule inhibitors also promoted the study of STAT3. Since STAT3 has been extensively studied in inflammation and tumor regulation, this review presents the current state of research on STAT3.
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Affiliation(s)
- Yang Sheng Hu
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China
| | - Xu Han
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China
| | - Xin Hua Liu
- School of Pharmacy, Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, 230032, China
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Wang L, Cheng J, Lin F, Liu S, Pan H, Li M, Li S, Li N, Li W. Ortho-Topolin Riboside Induced Differentiation through Inhibition of STAT3 Signaling in Acute Myeloid Leukemia HL-60 Cells. Turk J Haematol 2019; 36:162-168. [PMID: 31117333 PMCID: PMC6682775 DOI: 10.4274/tjh.galenos.2019.2019.0020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Objective: We previously demonstrated that ortho-topolin riboside (oTR) as a naturally occurring cytokinin secreted from Populus × robusta has great potential anticancer effects via the mitochondrial apoptotic pathway and endoplasmic reticulum stress pathway. In the present study, we reveal that oTR induced the differentiation of acute myeloid leukemia (AML) HL-60 cells, which represent the M2 subtype of AML. Materials and Methods: After the incubation of HL-60 cells with oTR, its effect was analyzed with cell viability assay, Wright-Giemsa staining, CD11b protein expression analysis, western blot analysis, and polymerase chain reaction. Results: We found that oTR arrested the cell cycle at the S phase, upregulated the expression of myeloid surface marker CD11b, reduced the nuclear cytoplasmic ratio, and altered the horseshoe shape of nuclei, as evidenced by Wright-Giemsa staining. Furthermore, we found that the protein level of phosphorylated STAT3 was decreased when cells were treated with oTR, while phosphorylated STAT1 was activated. Moreover, the protein level of phosphorylated STAT3 and its upstream kinase, Janus kinase 2, were also inhibited when cells were treated with oTR after increased time. Additionally, the levels of phosphorylated SHP-1 were increased while phosphorylated SHP-2 was decreased. Conclusion: Collectively, our data indicate a differentiation-induced mechanism underlying the inhibition of STAT3 signaling upon treatment with oTR. Therefore, oTR may constitute a novel differentiation-induced therapeutic for use in clinical treatment of AML.
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Affiliation(s)
- Li Wang
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - Jiao Cheng
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - FanLin Lin
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - ShengXian Liu
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - Hui Pan
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - MingDa Li
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - ShanShan Li
- School of Life and Medicine, Dalian University of Technology, PanJin, China
| | - Na Li
- The Second Hospital of Dalian Medical University, Dalian, China
| | - WeiPing Li
- The Second Hospital of Dalian Medical University, Dalian, China
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de Araújo Delmondes G, Bezerra DS, de Queiroz Dias D, de Souza Borges A, Araújo IM, Lins da Cunha G, Bandeira PFR, Barbosa R, Melo Coutinho HD, Felipe CFB, Barbosa-Filho JM, Alencar de Menezes IR, Kerntopf MR. Toxicological and pharmacologic effects of farnesol (C15H26O): A descriptive systematic review. Food Chem Toxicol 2019; 129:169-200. [DOI: 10.1016/j.fct.2019.04.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 04/02/2019] [Accepted: 04/22/2019] [Indexed: 12/22/2022]
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Ku M, MacKinnon RN, Wall M, Narayan N, Walkley C, Cheng HC, Campbell LJ, Purton LE, Nandurkar H. Hemopoietic Cell Kinase amplification with Protein Tyrosine Phosphatase Receptor T depletion leads to polycythemia, aberrant marrow erythoid maturation, and splenomegaly. Sci Rep 2019; 9:7050. [PMID: 31065022 PMCID: PMC6505535 DOI: 10.1038/s41598-019-43373-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 04/23/2019] [Indexed: 11/16/2022] Open
Abstract
Deletion of long arm of chromosome 20 [del(20q)] is the second most frequent recurrent chromosomal abnormality in hematological malignancies. It is detected in 10% of myeloproliferative neoplasms, 4-5% of myelodysplastic syndromes, and 1-2% of acute myeloid leukaemia. Recurrent, non-random occurrence of del(20q) indicates that it is a pathogenic driver in myeloid malignancies. Genetic mapping of patient samples has identified two regions of interest on 20q - the "Common Deleted Region" (CDR) and "Common Retained Region" (CRR), which was often amplified. We proposed that the CDR contained tumor suppressor gene(s) (TSG) and the CRR harbored oncogene(s); loss of a TSG together with over-expression of an oncogene favored development of myeloid malignancies. Protein Tyrosine Phosphatase Receptor T (PTPRT) and Hemopoietic cell kinase (HCK) were identified to be the likely candidate TSG and oncogene respectively. Retroviral transduction of HCK into PTPRT-null murine LKS+ stem and progenitor cells resulted in hyperproliferation in colony forming assays and hyperphosphorylation of intracellular STAT3. Furthermore, over half of the murine recipients of these transduced cells developed erythroid hyperplasia, polycythemia and splenomegaly at 12 months, although no leukemic phenotype was observed. The findings suggested that HCK amplification coupled with PTPRT loss in del(20q) leads to development of a myeloproliferative phenotype.
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Affiliation(s)
- Matthew Ku
- Department of Haematology, St Vincent's Hospital, 3065, Fitzroy, Australia.
- Department of Medicine, St Vincent's Hospital, The University of Melbourne, 3065, Fitzroy, Australia.
| | - Ruth N MacKinnon
- Victorian Cancer Cytogenetics Services, St Vincent's Hospital, 3065, Fitzroy, Australia
| | - Meaghan Wall
- Victorian Cancer Cytogenetics Services, St Vincent's Hospital, 3065, Fitzroy, Australia
| | - Nisha Narayan
- Department of Haematology, St Vincent's Hospital, 3065, Fitzroy, Australia
| | - Carl Walkley
- St Vincent's Institute of Medical Research, 3065, Fitzroy, Australia
- Department of Medicine, St Vincent's Hospital, The University of Melbourne, 3065, Fitzroy, Australia
| | | | - Lynda J Campbell
- Victorian Cancer Cytogenetics Services, St Vincent's Hospital, 3065, Fitzroy, Australia
| | - Louise E Purton
- St Vincent's Institute of Medical Research, 3065, Fitzroy, Australia
- Department of Medicine, St Vincent's Hospital, The University of Melbourne, 3065, Fitzroy, Australia
| | - Harshal Nandurkar
- Department of Medicine, St Vincent's Hospital, The University of Melbourne, 3065, Fitzroy, Australia
- The Australian Centre for Blood Diseases, Monash University, 3004, Melbourne, Australia
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Tan ZB, Fan HJ, Wu YT, Xie LP, Bi YM, Xu HL, Chen HM, Li J, Liu B, Zhou YC. Rheum palmatum extract exerts anti-hepatocellular carcinoma effects by inhibiting signal transducer and activator of transcription 3 signaling. JOURNAL OF ETHNOPHARMACOLOGY 2019; 232:62-72. [PMID: 30553869 DOI: 10.1016/j.jep.2018.12.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 12/06/2018] [Accepted: 12/12/2018] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hepatocellular carcinoma (HCC) is among the most common malignancies. Signal transducer and activator of transcription 3 (STAT3), with abnormal expression and constitutive activation, has been reported to promote proliferation, metastasis, survival and angiogenesis of HCC cells. Rheum palmatum (RP), a traditional Chinese medicinal herb, exhibited tumor-suppressing effects in multiple human cancers, but its potential functions in HCC remain unexplored. AIM OF THE STUDY This study aimed to examine the involvement of STAT3 signaling in the anti-HCC effects of RP extract. MATERIALS AND METHODS SMMC-7721 and HepG2 HCC cell lines were treated with RP extract for 24 h, and then viability, migration, and invasion of HCC cells and angiogenesis of human umbilical vein endothelial cells (HUVECs) were analyzed using MTS, wound-healing, Transwell invasion and tube formation assays, respectively. Western blotting and immunohistochemistry (IHC) were used to examine the activation of key molecules in STAT3 signaling, including STAT3, JAK2, and Src. Additionally, we explored the in vivo antitumor effects of RP extract in a xenograft tumor nude mouse model of HCC. RESULTS The result showed that RP extract reduced viability, migration, and invasion of SMMC-7721 and HepG2 cells and angiogenesis of HUVECs. It suppressed the phosphorylation of STAT3 and its upstream kinases including JAK2 and Src. In addition, RP extract treatment downregulated STAT3 target genes, including survivin, Bcl-xL, Mcl-1, Bcl-2, MMP-2, MMP-9, Cyclin D1, CDK4, c-Myc, and VEGF-C. Furthermore, RP extract suppressed the xenograft tumor growth and activation of STAT3 in xenograft tumor mice. CONCLUSION Collectively, the results showed that RP extract prevented HCC progression by inhibiting STAT3, and might be useful for the treatment of HCC.
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MESH Headings
- Animals
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Survival/drug effects
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/physiology
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Mice, Inbred BALB C
- Mice, Nude
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/metabolism
- Plant Extracts/pharmacology
- Plant Extracts/therapeutic use
- Rheum
- STAT3 Transcription Factor/metabolism
- Signal Transduction/drug effects
- Wound Healing/drug effects
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Affiliation(s)
- Zhang-Bin Tan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Hui-Jie Fan
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Yu-Ting Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Ling-Peng Xie
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Yi-Ming Bi
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Hong-Lin Xu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Hong-Mei Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Jun Li
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Bin Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
| | - Ying-Chun Zhou
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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24
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Cycloxygenase-2 inhibition potentiates trans-differentiation of Wharton's jelly–mesenchymal stromal cells into endothelial cells: Transplantation enhances neovascularization-mediated wound repair. Cytotherapy 2019; 21:260-273. [DOI: 10.1016/j.jcyt.2019.01.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 12/23/2018] [Accepted: 01/12/2019] [Indexed: 01/08/2023]
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25
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Shen K, Moroco JA, Patel RK, Shi H, Engen JR, Dorman HR, Smithgall TE. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation. Sci Signal 2018; 11:11/553/eaat5916. [DOI: 10.1126/scisignal.aat5916] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, we investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.
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26
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Kim C, Lee SG, Yang WM, Arfuso F, Um JY, Kumar AP, Bian J, Sethi G, Ahn KS. Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model. Cancer Lett 2018; 431:123-141. [DOI: 10.1016/j.canlet.2018.05.038] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 05/23/2018] [Accepted: 05/23/2018] [Indexed: 01/13/2023]
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Xing Y, Mi C, Wang Z, Zhang ZH, Li MY, Zuo HX, Wang JY, Jin X, Ma J. Fraxinellone has anticancer activity in vivo by inhibiting programmed cell death-ligand 1 expression by reducing hypoxia-inducible factor-1α and STAT3. Pharmacol Res 2018; 135:166-180. [PMID: 30103001 DOI: 10.1016/j.phrs.2018.08.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/21/2018] [Accepted: 08/06/2018] [Indexed: 12/11/2022]
Abstract
Dictamnus dasycarpus is a traditional Chinese medicine thathas been commonly used in the treatment of cancer. Fraxinellone is a natural product isolated from the D. dasycarpus plant, which has been shown to exhibit neuroprotective and anti-inflammatory activities. However, whether fraxinellone exerts anticancer effects and the mechanisms by which it may inhibit tumor growth remain unknown. Here, we found that fraxinellone, in a dose-dependented manner, inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis. It was subsequently shown that fraxinellone reduced HIF-1α protein synthesis via the mTOR/p70S6K/eIF4E and MAPK pathways. It also inhibited activation of STAT3 via the JAK1, JAK2, and Src pathways. Immunoprecipitation and western blotting assays showed that fraxinellone inhibited PD-L1 expression by reducing STAT3 and HIF-1α cooperatively. Flow cytometry, colony formation, and EdU incorporation assays demonstrated that fraxinellone inhibited cell proliferation through suppression of PD-L1. Tube formation, migration, and invasion assays showed that fraxinellone inhibits angiogenesis by suppressing PD-L1. In vivo studies further supported anticancer role for fraxinellone, demonstrating that fraxinellone treatment inhibited the growth of tumor xenografts. We concluded that fraxinellone inhibits PD-L1 expression by downregulating the STAT3 and HIF-1α signaling pathways, subsequently inhibiting proliferation and angiogenesis in cancer cells. These studies reveal previously unknown characteristics of fraxinellone and provide new perspectives into the mechanism of cancer inhibition of the compound.
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Affiliation(s)
- Yue Xing
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Chunliu Mi
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhe Wang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhi Hong Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Ming Yue Li
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Hong Xiang Zuo
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Jing Ying Wang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Xuejun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
| | - Juan Ma
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
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Mei J, Zhou WJ, Zhu XY, Lu H, Wu K, Yang HL, Fu Q, Wei CY, Chang KK, Jin LP, Wang J, Wang YM, Li DJ, Li MQ. Suppression of autophagy and HCK signaling promotes PTGS2 high FCGR3 - NK cell differentiation triggered by ectopic endometrial stromal cells. Autophagy 2018; 14:1376-1397. [PMID: 29962266 DOI: 10.1080/15548627.2018.1476809] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Impaired NK cell cytotoxic activity contributes to the local dysfunctional immune environment in endometriosis (EMS), which is an estrogen-dependent gynecological disease that affects the function of ectopic endometrial tissue clearance. The reason for the impaired cytotoxic activity of NK cells in an ectopic lesion microenvironment (ELM) is largely unknown. In this study, we show that the macroautophagy/autophagy level of endometrial stromal cells (ESCs) from EMS decreased under negative regulation of estrogen. The ratio of peritoneal FCGR3- NK to FCGR3+ NK cells increases as EMS progresses. Moreover, the autophagy suppression results in the downregulation of HCK (hematopoietic cellular kinase) by inactivating STAT3 (signal transducer and activator of transcription 3), as well as the increased secretion of the downstream molecules CXCL8/IL8 and IL23A by ESCs, and this increase induced the upregulation of FCGR3- NK cells and decline of cytotoxic activity in ELM. This process is mediated through the depression of microRNA MIR1185-1-3p, which is associated with the activation of the target gene PTGS2 in NK cells. FCGR3- NK with a phenotype of PTGS2/COX2high IFNGlow PRF1low GZMBlow induced by hck knockout (hck-/-) or 3-methyladenine (3-MA, an autophagy inhibitor)-stimulated ESCs accelerates ESC's growth both in vitro and in vivo. These results suggest that the estrogen-autophagy-STAT3-HCK axis participates in the differentiation of PTGS2high IFNGlow PRF1low GZMBlow FCGR3- NK cells in ELM and contributes to the development of EMS. This result provides a scientific basis for potential therapeutic strategies to treat diseases related to impaired NK cell cytotoxic activity. ABBREVIATIONS anti-FCGR3: anti-FCGR3 with neutralizing antibody; Ctrl-ESC: untreated ESCs; CXCL8: C-X-C motif chemokine ligand 8; ectoESC: ESCs from ectopic lesion; ELM: ectopic lesion microenvironment; EMS: endometriosis; ESCs: endometrial stromal cells; eutoESC:eutopic ESCs; HCK: hematopoietic cellular kinase; HCK(OE): overexpression of HCK; IFNG: interferon gamma; IL23A (OE): overexpression of IL23A; KLRK1: Killer cell lectin like receptor K1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; 3 -MA: 3-methyladenine; 3-MA-ESC: 3-MA-treated ESCs; MIR1185-1-3p+: overexpression of HsMIR1185-1-3p; NK: natural killer; normESCs: normal ESCs; Rap-ESC:rapamycin-treated ESCs; PCNA: proliferating cell nuclear antigen; PF: peritoneal fluid; SFKs: SRC family of cytoplasmic tyrosine kinases; si-HCK: silencing of HCK; siIL23A: silencing of IL23A; USCs: uterus stromal cells.
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Affiliation(s)
- Jie Mei
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China.,b Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital , The Affiliated Hospital of Nanjing University Medicine School , Nanjing , People's Republic of China
| | - Wen-Jie Zhou
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Xiao-Yong Zhu
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China.,c Department of Gynecology, Hospital of Obstetrics and Gynecology, Shanghai Medical School , Fudan University , Shanghai , People's Republic of China
| | - Han Lu
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Ke Wu
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Hui-Li Yang
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Qiang Fu
- d Department of Immunology , Binzhou Medical College , Yantai , People's Republic of China
| | - Chun-Yan Wei
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Kai-Kai Chang
- b Reproductive Medicine Center, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital , The Affiliated Hospital of Nanjing University Medicine School , Nanjing , People's Republic of China
| | - Li-Ping Jin
- e Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital , Tongji University School of Medicine , Shanghai , People's Republic of China
| | - Jian Wang
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Yong-Ming Wang
- f State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences , Fudan University , Shanghai , People's Republic of China
| | - Da-Jin Li
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
| | - Ming-Qing Li
- a Laboratory for Reproductive Immunology, Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology , Fudan University Shanghai Medical College , Shanghai , People's Republic of China
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Galoczova M, Coates P, Vojtesek B. STAT3, stem cells, cancer stem cells and p63. Cell Mol Biol Lett 2018; 23:12. [PMID: 29588647 PMCID: PMC5863838 DOI: 10.1186/s11658-018-0078-0] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 03/07/2018] [Indexed: 12/15/2022] Open
Abstract
Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor with many important functions in the biology of normal and transformed cells. Its regulation is highly complex as it is involved in signaling pathways in many different cell types and under a wide variety of conditions. Besides other functions, STAT3 is an important regulator of normal stem cells and cancer stem cells. p63 which is a member of the p53 protein family is also involved in these functions and is both physically and functionally connected with STAT3. This review summarizes STAT3 function and regulation, its role in stem cell and cancer stem cell properties and highlights recent reports about its relationship to p63.
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Affiliation(s)
- Michaela Galoczova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic
| | - Philip Coates
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic
| | - Borivoj Vojtesek
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic
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30
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Park J, Kim S, Joh J, Remick SC, Miller DM, Yan J, Kanaan Z, Chao JH, Krem MM, Basu SK, Hagiwara S, Kenner L, Moriggl R, Bunting KD, Tse W. MLLT11/AF1q boosts oncogenic STAT3 activity through Src-PDGFR tyrosine kinase signaling. Oncotarget 2018; 7:43960-43973. [PMID: 27259262 PMCID: PMC5190071 DOI: 10.18632/oncotarget.9759] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 04/29/2016] [Indexed: 01/05/2023] Open
Abstract
Constitutive STAT3 activation by tyrosine phosphorylation of mutated or amplified tyrosine kinases (pYSTAT3) is critical for cancer initiation, progression, invasion, and motility of carcinoma cells. We showed that AF1q is associated with STAT3 signaling in breast cancer cells. In xenograft models, enhanced AF1q expression activated STAT3 and promoted tumor growth and metastasis in immunodeficient NSG mice. The cytokine secretory phenotype of MDA-MB-231LN breast cancer cells with altered AF1q expression revealed changes in expression of platelet-derived growth factor subunit B (PDGF-B). AF1q-induced PDGF-B stimulated motility, migration, and invasion of MDA-MB-231LN cells, and AF1q up-regulated platelet-derived growth factor receptor (PDGFR) signaling. Further, AF1q-induced PDGFR signaling enhanced STAT3 activity through Src kinase activation, which could be blocked by the Src kinase inhibitor PP1. Moreover, AF1q up-regulated tyrosine kinase signaling through PDGFR signaling, which was blockable by imatinib. In conclusion, we demonstrated that enhanced AF1q expression contributes to persistent and oncogenic pYSTAT3 levels in invasive carcinoma cells by activating Src kinase through activation of the PDGF-B/PDGFR cascade. Therefore, AF1q plays an essential role as a cofactor in PDGF-B-driven STAT3 signaling.
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Affiliation(s)
- Jino Park
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Soojin Kim
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Joongho Joh
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
| | - Scot C Remick
- Maine Medical Center Research Institute, Portland, ME, USA
| | - Donald M Miller
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jun Yan
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Department of Medicine and Department of Microbiology and Immunology, University of Louisville, Louisville, KY, USA
| | - Zeyad Kanaan
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA
| | - Ju-Hsien Chao
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Maxwell M Krem
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Soumit K Basu
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
| | - Shotaro Hagiwara
- Division of Hematology, Internal Medicine, National Center for Global Health and Medicine, Shinjuku, Japan
| | - Lukas Kenner
- Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.,Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria.,Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria
| | - Richard Moriggl
- Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.,Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Medical University of Vienna, Vienna, Austria
| | - Kevin D Bunting
- Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA
| | - William Tse
- James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Blood and Bone Marrow Transplantation, Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
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31
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Mi C, Ma J, Wang KS, Wang Z, Li MY, Li JB, Li X, Piao LX, Xu GH, Jin X. Amorfrutin A inhibits TNF-α induced JAK/STAT signaling, cell survival and proliferation of human cancer cells. Immunopharmacol Immunotoxicol 2017; 39:338-347. [PMID: 28879797 DOI: 10.1080/08923973.2017.1371187] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
CONTEXT Amorfrutin A is a natural product isolated from the fruits of Amorpha fruticosa L. and has been shown to exhibit multiple bioeffector functions. In the present study, we investigated whether amorfrutin A exerts anticancer effects by inhibiting STAT3 activation in cervical cancer cells. OBJECTIVE To investigate the effectiveness of amorfrutin A as a treatment of cancer, and determine the underlying pharmacological mechanism of action. MATERIALS AND METHODS HeLa, SK-Hep1, MDA-MB-231 and HCT116 cells were used in this study. Major assays were luciferase reporter assay, MTT, Western blot analysis, immunofluorescence assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, EdU labeling and immunofluorescence, xenografted assay. RESULTS Amorfrutin A significantly inhibited tumor necrosis factor-α (TNF-α)-induced phosphorylation and nuclear translocation of STAT3 in human cervical carcinoma cells. Amorfrutin A also inhibited activation of the upstream kinases Janus-activated kinase 1 (JAK1), JAK2 and Src signaling pathways. Furthermore, amorfrutin A increased the expression of p53, p21, p27, induced cell cycle arrest in the G1 phase as well as decreased levels of various oncogene protein products. In vivo studies further confirmed the inhibitory effect of amorfrutin A on the expression of STAT3 proteins, leading to a decrease growth of HeLa cells in a xenograft tumor model. DISCUSSION AND CONCLUSIONS The results indicated that amorfrutin A is a potent inhibitor of STAT3 and provide new perspectives into the mechanism of its anticancer activity.
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Affiliation(s)
- Chunliu Mi
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Juan Ma
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Ke Si Wang
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Zhe Wang
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Ming Yue Li
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Jun Bo Li
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Xuezheng Li
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Lian Xun Piao
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Guang Hua Xu
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
| | - Xuejun Jin
- a Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, Molecular Medicine Research Center, College of Pharmacy , Yanbian University , Yanji , China
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Kim JH, Park B. Triptolide blocks the STAT3 signaling pathway through induction of protein tyrosine phosphatase SHP-1 in multiple myeloma cells. Int J Mol Med 2017; 40:1566-1572. [DOI: 10.3892/ijmm.2017.3122] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 08/25/2017] [Indexed: 11/06/2022] Open
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33
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Chuang YF, Huang SW, Hsu YF, Yu MC, Ou G, Huang WJ, Hsu MJ. WMJ-8-B, a novel hydroxamate derivative, induces MDA-MB-231 breast cancer cell death via the SHP-1-STAT3-survivin cascade. Br J Pharmacol 2017. [PMID: 28646512 DOI: 10.1111/bph.13929] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND AND PURPOSE Histone deacetylase (HDAC) inhibitors have been demonstrate to have broad-spectrum anti-tumour properties and have attracted lots of attention in the field of drug discovery. However, the underlying anti-tumour mechanisms of HDAC inhibitors remain incompletely understood. In this study, we aimed to characterize the underlying mechanisms through which the novel hydroxamate-based HDAC inhibitor, WMJ-8-B, induces the death of MDA-MB-231 breast cancer cells. EXPERIMENTAL APPROACH Effects of WMJ-8-B on cell viability, cell cycle distribution, apoptosis and signalling molecules were analysed by the MTT assay, flowcytometric analysis, immunoblotting, reporter assay, chromatin immunoprecipitation analysis and use of siRNAs. A xenograft model was used to determine anti-tumour effects of WMJ-8-B in vivo. KEY RESULTS WMJ-8-B induced survivin reduction, G2/M cell cycle arrest and apoptosis in MDA-MB-231 cells. STAT3 phosphorylation, transactivity and its binding to the survivin promoter region were reduced in WMJ-8-B-treated cells. WMJ-8-B activated the protein phosphatase SHP-1 and when SHP-1 signalling was blocked, the effects of WMJ-8-B on STAT3 phosphorylation and survivin levels were abolished. However, WMJ-8-B increased the transcription factor Sp1 binding to the p21 promoter region and enhanced p21 levels. Moreover, WMJ-8-B induced α-tubulin acetylation and disrupted microtubule assembly. Inhibition of HDACs was shown to contribute to WMJ-8-B's actions. Furthermore, WMJ-8-B suppressed the growth of MDA-MB-231 xenografts in mammary fat pads in vivo. CONCLUSIONS AND IMPLICATIONS The SHP-1-STAT3-survivin and Sp1-p21 cascades are involved in WMJ-8-B-induced MDA-MB-231 breast cancer cell death. These results also indicate the potential of WMJ-8-B as a lead compound for treatment of breast cancer and warrant its clinical development.
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Affiliation(s)
- Yu-Fan Chuang
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shiu-Wen Huang
- Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Fen Hsu
- Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan
| | - Meng-Chieh Yu
- Division of General Surgery, Department of Surgery, Landseed Hospital, Taoyuan, Taiwan.,Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - George Ou
- Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Wei-Jan Huang
- Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
| | - Ming-Jen Hsu
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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A muscle-specific protein 'myoferlin' modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus. Oncogene 2017; 36:6374-6382. [PMID: 28745314 PMCID: PMC5690845 DOI: 10.1038/onc.2017.245] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 05/08/2017] [Accepted: 06/12/2017] [Indexed: 01/03/2023]
Abstract
Myoferlin, a member of ferlin family of proteins, was first discovered as a candidate gene for muscular dystrophy and cardiomyopathy. Recently, myoferlin was shown to be also expressed in endothelial and cancer cells where it was shown to modulate vascular endothelial growth factor (VEGFR)-2 and epidermal growth factor receptor (EGFR) signaling by enhancing their stability and recycling. Based on these reports, we hypothesized that myoferlin might be regulating IL-6 signaling by modulating IL-6R stabilization and recycling. However, in our immunoprecipitation (IP) experiments, we did not observe myoferlin binding with IL-6R. Instead, we made a novel discovery that in resting cells myoferlin was bound to EHD2 protein and when cells were treated with IL-6, myoferlin dissociated from EHD2 and binds to activated STAT3. Interestingly, myoferlin depletion did not affect STAT3 phosphorylation, but completely blocked STAT3 translocation to nucleus. In addition, inhibition of STAT3 phosphorylation by phosphorylation-defective STAT3 mutants or JAK inhibitor blocked STAT3 binding to myoferlin and nuclear translocation. Myoferlin knockdown significantly decreased IL-6-mediated tumor cell migration, tumorsphere formation and ALDH-positive cancer stem cell population, in vitro. Furthermore, myoferlin knockdown significantly decreased IL-6-meditated tumor growth and tumor metastasis. Based on these results, we have proposed a novel model for the role of myoferlin in chaperoning phosphorylated STAT3 to the nucleus.
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35
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Li T, Fu X, Tse AKW, Guo H, Lee KW, Liu B, Su T, Wang X, Yu Z. Inhibiting STAT3 signaling is involved in the anti-melanoma effects of a herbal formula comprising Sophorae Flos and Lonicerae Japonicae Flos. Sci Rep 2017; 7:3097. [PMID: 28596565 PMCID: PMC5465088 DOI: 10.1038/s41598-017-03351-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 04/26/2017] [Indexed: 12/14/2022] Open
Abstract
A herbal formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was traditionally used to treat melanoma. Constitutively active signal transducer and activator of transcription 3 (STAT3) has been proposed as a therapeutic target in melanoma. Here we investigated whether an ethanolic extract of SL (SLE) exerted anti-melanoma activities by inhibiting STAT3 signaling. B16F10 allograft model, A375 and B16F10 cells were employed to assess the in vivo and in vitro anti-melanoma activities of SLE. A375 cells stably expressing STAT3C, a constitutively active STAT3 mutant, were used to determine the role of STAT3 signaling in SLE’s anti-melanoma effects. Intragastric administration of SLE (1.2 g/kg) potently inhibited melanoma growth in mice and inhibited STAT3 phosphorylation in the tumors. In cultured cells, SLE dramatically reduced cell viability, induced apoptosis, suppressed migration and invasion, and restrained STAT3 activation and nuclear localization. STAT3C overexpression in A375 cells diminished SLE’s effects on cell viability, apoptosis and invasion. Collectively, SLE exerted potent anti-melanoma effects partially by inhibiting STAT3 signaling. This study provides pharmacological justification for the traditional use of this formula in treating melanoma, and suggests that SLE has the potential to be developed as a modern alternative and/or complimentary agent for melanoma treatment and prevention.
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Affiliation(s)
- Ting Li
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xiuqiong Fu
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Anfernee Kai-Wing Tse
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Hui Guo
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Kin Wah Lee
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Bin Liu
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Tao Su
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Xueyu Wang
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Zhiling Yu
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. .,Research and Development Centre for Natural Health Products, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China.
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36
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Liu C, Su J, Huang T, Chu P, Huang C, Wang W, Lee C, Lau K, Tsai W, Yang H, Shiau C, Tseng L, Chen K. Sorafenib analogue SC-60 induces apoptosis through the SHP-1/STAT3 pathway and enhances docetaxel cytotoxicity in triple-negative breast cancer cells. Mol Oncol 2017; 11:266-279. [PMID: 28084011 PMCID: PMC5527447 DOI: 10.1002/1878-0261.12033] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 01/09/2017] [Accepted: 01/09/2017] [Indexed: 01/08/2023] Open
Abstract
Recurrent triple-negative breast cancer (TNBC) needs new therapeutic targets. Src homology region 2 domain-containing phosphatase-1 (SHP-1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP-1 is STAT3, which is highly activated in TNBC. In this study, we tested a sorafenib analogue SC-60, which lacks angiokinase inhibition activity, but acts as a SHP-1 agonist, in TNBC cells. SC-60 inhibited proliferation and induced apoptosis by dephosphorylating STAT3 in both a dose- and time-dependent manner in TNBC cells (MDA-MB-231, MDA-MB-468, and HCC1937). By contrast, ectopic expression of STAT3 rescued the anticancer effect induced by SC-60. SC-60 also increased the SHP-1 activity, but this effect was inhibited when the N-SH2 domain (DN1) was deleted or with SHP-1 point mutation (D61A), implying that SHP-1 is the major target of SC-60 in TNBC. The use of SC-60 in combination with docetaxel synergized the anticancer effect induced by SC-60 through the SHP-1/STAT3 pathway in TNBC cells. Importantly, SC-60 also displayed a significant antitumor effect in an MDA-MB-468 xenograft model by modulating the SHP-1/STAT3 axis, indicating the anticancer potential of SC-60 in TNBC treatment. Targeting SHP-1/p-STAT3 and the potential combination of SHP-1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC.
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Affiliation(s)
- Chun‐Yu Liu
- Comprehensive Breast Health CenterTaipei Veterans General HospitalTaiwan
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
- School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Jung‐Chen Su
- Institute of Biopharmaceutical SciencesNational Yang‐Ming UniversityTaipeiTaiwan
- Department of Clinical Laboratory Sciences and Medical BiotechnologyNational Taiwan UniversityTaipeiTaiwan
| | - Tzu‐Ting Huang
- Comprehensive Breast Health CenterTaipei Veterans General HospitalTaiwan
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
| | - Pei‐Yi Chu
- Department of PathologyShow Chwan Memorial HospitalChanghuaTaiwan
- School of MedicineCollege of MedicineFu‐Jen Catholic UniversityXinzhuangNew Taipei CityTaiwan
| | - Chun‐Teng Huang
- School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Division of Hematology & OncologyDepartment of MedicineYang‐Ming Branch of Taipei City HospitalTaiwan
| | - Wan‐Lun Wang
- Department of SurgeryTaipei Veterans General HospitalTaiwan
| | - Chia‐Han Lee
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
| | - Ka‐Yi Lau
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
| | - Wen‐Chun Tsai
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
| | - Hsiu‐Ping Yang
- Division of Medical OncologyDepartment of OncologyTaipei Veterans General HospitalTaiwan
| | - Chung‐Wai Shiau
- Institute of Biopharmaceutical SciencesNational Yang‐Ming UniversityTaipeiTaiwan
| | - Ling‐Ming Tseng
- Comprehensive Breast Health CenterTaipei Veterans General HospitalTaiwan
- School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Department of SurgeryTaipei Veterans General HospitalTaiwan
| | - Kuen‐Feng Chen
- Department of Medical ResearchNational Taiwan University HospitalTaipeiTaiwan
- National Taiwan University College of MedicineTaipeiTaiwan
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Siavash H, Nikitakis N, Sauk J. Signal Transducers and Activators of Transcription: Insights into the Molecular Basis of Oral Cancer. ACTA ACUST UNITED AC 2016; 15:298-307. [DOI: 10.1177/154411130401500505] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Recent efforts on developing more direct and effective targets for cancer therapy have revolved around a family of transcription factors known as STATs (signal transducers and activators of transcription). STAT proteins are latent cytoplasmic transcription factors that become activated in response to extracellular signaling proteins. STAT proteins have been convincingly reported to possess oncogenic properties in a plethora of human cancers, including oral and oropharyngeal cancer. Signal transduction pathways mediated by these oncogenic transcription factors and their regulation in oral cancer are the focus of this review.
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Affiliation(s)
- H. Siavash
- Department of Biomedical Sciences and
- Department of Diagnostic Sciences and Pathology, University of Maryland, Dental School, 666 West Baltimore Street, Room 4-C-02, Baltimore, MD 21201; and
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201
| | - N.G. Nikitakis
- Department of Biomedical Sciences and
- Department of Diagnostic Sciences and Pathology, University of Maryland, Dental School, 666 West Baltimore Street, Room 4-C-02, Baltimore, MD 21201; and
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201
| | - J.J. Sauk
- Department of Biomedical Sciences and
- Department of Diagnostic Sciences and Pathology, University of Maryland, Dental School, 666 West Baltimore Street, Room 4-C-02, Baltimore, MD 21201; and
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201
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Ko JH, Ho Baek S, Nam D, Chung WS, Lee SG, Lee J, Mo Yang W, Um JY, Seok Ahn K. 3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3. Immunopharmacol Immunotoxicol 2016; 38:334-43. [DOI: 10.1080/08923973.2016.1203928] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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RIG-I inhibits pancreatic β cell proliferation through competitive binding of activated Src. Sci Rep 2016; 6:28914. [PMID: 27349479 PMCID: PMC4923948 DOI: 10.1038/srep28914] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 06/10/2016] [Indexed: 02/06/2023] Open
Abstract
Nutrition is a necessary condition for cell proliferation, including pancreatic β cells; however, over-nutrition, and the resulting obesity and glucolipotoxicity, is a risk factor for the development of Type 2 diabetes mellitus (DM), and causes inhibition of pancreatic β-cells proliferation and their loss of compensation for insulin resistance. Here, we showed that Retinoic acid (RA)-inducible gene I (RIG-I) responds to nutrient signals and induces loss of β cell mass through G1 cell cycle arrest. Risk factors for type 2 diabetes (e.g., glucolipotoxicity, TNF-α and LPS) activate Src in pancreatic β cells. Elevated RIG-I modulated the interaction of activated Src and STAT3 by competitive binding to STAT3. Elevated RIG-I downregulated the transcription of SKP2, and increased the stability and abundance of P27 protein in a STAT3-dependent manner, which was associated with inhibition of β cell growth elicited by Src. These results supported a role for RIG-I in β cell mass loss under conditions of metabolic surplus and suggested that RIG-I-induced blocking of Src/STAT3 signalling might be involved in G1 phase cycle arrest through the Skp2/P27 pathway in pancreatic β cells.
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40
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Joosten M, Ginzel S, Blex C, Schmidt D, Gombert M, Chen C, Linka RM, Gräbner O, Hain A, Hirsch B, Sommerfeld A, Seegebarth A, Gruber U, Maneck C, Zhang L, Stenin K, Dieks H, Sefkow M, Münk C, Baldus CD, Thiele R, Borkhardt A, Hummel M, Köster H, Fischer U, Dreger M, Seitz V. A novel approach to detect resistance mechanisms reveals FGR as a factor mediating HDAC inhibitor SAHA resistance in B-cell lymphoma. Mol Oncol 2016; 10:1232-44. [PMID: 27324824 DOI: 10.1016/j.molonc.2016.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Revised: 06/02/2016] [Accepted: 06/03/2016] [Indexed: 01/15/2023] Open
Abstract
Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are not commonly used in clinical practice for treatment of B-cell lymphomas, although a subset of patients with refractory or relapsed B-cell lymphoma achieved partial or complete remissions. Therefore, the purpose of this study was to identify molecular features that predict the response of B-cell lymphomas to SAHA treatment. We designed an integrative approach combining drug efficacy testing with exome and captured target analysis (DETECT). In this study, we tested SAHA sensitivity in 26 B-cell lymphoma cell lines and determined SAHA-interacting proteins in SAHA resistant and sensitive cell lines employing a SAHA capture compound (CC) and mass spectrometry (CCMS). In addition, we performed exome mutation analysis. Candidate validation was done by expression analysis and knock-out experiments. An integrated network analysis revealed that the Src tyrosine kinase Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog (FGR) is associated with SAHA resistance. FGR was specifically captured by the SAHA-CC in resistant cells. In line with this observation, we found that FGR expression was significantly higher in SAHA resistant cell lines. As functional proof, CRISPR/Cas9 mediated FGR knock-out in resistant cells increased SAHA sensitivity. In silico analysis of B-cell lymphoma samples (n = 1200) showed a wide range of FGR expression indicating that FGR expression might help to stratify patients, which clinically benefit from SAHA therapy. In conclusion, our comprehensive analysis of SAHA-interacting proteins highlights FGR as a factor involved in SAHA resistance in B-cell lymphoma.
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Affiliation(s)
- Maria Joosten
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Sebastian Ginzel
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany; Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Grantham-Allee 20, 53757 Sankt Augustin, Germany
| | - Christian Blex
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Dmitri Schmidt
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Michael Gombert
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Cai Chen
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - René Martin Linka
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Olivia Gräbner
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Anika Hain
- Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Burkhard Hirsch
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Anke Sommerfeld
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Anke Seegebarth
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Uschi Gruber
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Corinna Maneck
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Langhui Zhang
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany; Department of Hematology, Union Hospital, Fujian Medical University, NO.29,Xinquan Road, Fuzhou City, Fujian Province, China
| | - Katharina Stenin
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Henrik Dieks
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Michael Sefkow
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Carsten Münk
- Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Claudia D Baldus
- Department of Hematology and Oncology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Ralf Thiele
- Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Grantham-Allee 20, 53757 Sankt Augustin, Germany
| | - Arndt Borkhardt
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Michael Hummel
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
| | - Hubert Köster
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Ute Fischer
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Center of Child and Adolescent Health, Medical Faculty, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany
| | - Mathias Dreger
- caprotec bioanalytics GmbH, Magnusstraße 11, 12489 Berlin, Germany
| | - Volkhard Seitz
- Institute of Pathology, Charité University Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
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Kim C, Lee IH, Hyun HB, Kim JC, Gyawali R, Lee SG, Lee J, Kim SH, Shim BS, Cho SK, Ahn KS. Supercritical Fluid Extraction of Citrus iyo Hort. ex Tanaka Pericarp Inhibits Growth and Induces Apoptosis Through Abrogation of STAT3 Regulated Gene Products in Human Prostate Cancer Xenograft Mouse Model. Integr Cancer Ther 2016; 16:227-243. [PMID: 27185319 PMCID: PMC5739124 DOI: 10.1177/1534735416649659] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Activation of signal transducer and activator of transcription 3 (STAT3) is well known to play a major role in the cell growth, survival, proliferation, metastasis, and angiogenesis of various cancer cells. Most of the citrus species offer large quantities of phytochemicals that have beneficial effects attributed to their chemical components. Our study was carried out to evaluate the anticancer effects of the pericarp of Iyokan ( Citrus iyo Hort. ex Tanaka), locally known as yeagam in Korea, through modulation of the STAT3 signaling pathway in both tumor cells and a nude mice model. The effect of supercritical extracts of yeagam peel (SEYG) on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of SEYG on the growth of DU145 human prostate xenograft tumors in athymic nu/nu male mice was also investigated. We found SEYG exerted substantial inhibitory effect on STAT3 activation in human prostate cancer DU145 cells as compared to other tumor cells analyzed. SEYG inhibited proliferation and downregulated the expression of various STAT3-regulated gene products such as bcl-2, bcl-xL, survivin, IAP-1/2, cyclin D1, cyclin E, COX-2, VEGF, and MMP-9. This correlated with an increase in apoptosis as indicated by an increase in the expression of p53 and p21 proteins, the sub-G1 arrest, and caspase-3-induced PARP cleavage. When administered intraperitoneally, SEYG reduced the growth of DU145 human prostate xenograft tumors through downmodulation of STAT3 activation in athymic nu/nu male mice. Overall, these results suggest that SEYG extract has the potential source of STAT3 inhibitors that may have a potential in chemoprevention of human prostate cancer cells.
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Affiliation(s)
- Chulwon Kim
- 1 Kyung Hee University, Seoul, Republic of Korea
| | - Il Ho Lee
- 1 Kyung Hee University, Seoul, Republic of Korea
| | - Ho Bong Hyun
- 2 Jeju National University, Jeju, Republic of Korea
| | - Jong-Chan Kim
- 3 Korea Food Research Institute, Seongnam, Gyeonggi-do, Republic of Korea
| | | | | | - Junhee Lee
- 1 Kyung Hee University, Seoul, Republic of Korea
| | | | | | - Somi K Cho
- 2 Jeju National University, Jeju, Republic of Korea
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Baek SH, Ko JH, Lee H, Jung J, Kong M, Lee JW, Lee J, Chinnathambi A, Zayed ME, Alharbi SA, Lee SG, Shim BS, Sethi G, Kim SH, Yang WM, Um JY, Ahn KS. Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2016; 23:566-577. [PMID: 27064016 DOI: 10.1016/j.phymed.2016.02.011] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/12/2016] [Accepted: 02/15/2016] [Indexed: 06/05/2023]
Abstract
BACKGROUND Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division. HYPOTHESIS Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models. STUDY DESIGN The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated. METHODS We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells. RESULTS We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment. CONCLUSION Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.
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Affiliation(s)
- Seung Ho Baek
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Jeong-Hyeon Ko
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Hanwool Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Jinhong Jung
- Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-872, Republic of Korea
| | - Moonkyoo Kong
- Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-872, Republic of Korea
| | - Jung-woo Lee
- Department of Oral & Maxillofacial Surgery, Kyung Hee University Dental Hospital, Kyung Hee University School of Dentistry, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872, Republic of Korea
| | - Junhee Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - M E Zayed
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sulaiman Ali Alharbi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Seok-Geun Lee
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Bum Sang Shim
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Gautam Sethi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore
| | - Sung-Hoon Kim
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Woong Mo Yang
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Jae-Young Um
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea
| | - Kwang Seok Ahn
- College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
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Zhu WQ, Wang J, Guo XF, Liu Z, Dong WG. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J Gastroenterol 2016; 22:4149-4159. [PMID: 27122665 PMCID: PMC4837432 DOI: 10.3748/wjg.v22.i16.4149] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Revised: 02/26/2016] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate the mechanism of thymoquinone (TQ)-induced apoptosis in human gastric cancer cells in vitro and in vivo.
METHODS: HGC27, BGC823, and SGC7901 cells were cultured in vitro and treated with TQ (0, 10, 25, 50, 75, 100, 125 μmol/L) for 12 h, 24 h, and 36 h, and then the proliferation inhibitory rates were detected by methylthiazole tetrazolium assay. Apoptosis was observed after Hoechst staining. The protein expressions of signal transducer and activator of transcription (STAT)3, p-STAT3, STAT5, p-STAT5, phospho-janus-activated kinase 2 (JAK2), JAK2, p-Src, Src, glyceraldehyde-3-phosphate dehydrogenase, lamin-A, survivin, Cyclin D, Bcl-2, Bax, peroxisome proliferator activated receptor, and caspase-3,7,9 were detected by western blot. Cell cycle and apoptosis were determined with flow cytometry. TQ induced dose-dependent apoptotic cell death in HGC27 cells was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) analysis and Hoechst 33258.
RESULTS: TQ inhibited the phosphorylation of STAT3 but not STAT5. TQ-induced downregulation of STAT3 activation was associated with a reduction in JAK2 and c-Src activity. TQ also downregulated the expression of STAT3-regulated genes, such as Bcl-2, cyclin D, survivin, and vascular endothelial growth factor, and activated caspase-3,7,9. Consistent with the in vitro results, TQ was significantly effective as an antitumor agent in a xenograft tumor mouse model.
CONCLUSION: This study provides strong evidence that downregulation of the STAT3 signaling pathway mediates TQ-induced apoptosis in gastric cancer.
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Blockage of STAT3 Signaling Pathway by Morusin Induces Apoptosis and Inhibits Invasion in Human Pancreatic Tumor Cells. Pancreas 2016; 45:409-19. [PMID: 26646273 DOI: 10.1097/mpa.0000000000000496] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor implicated in carcinogenesis. Here, we investigated the role of morusin, the major prenylflavonoid, isolated from Chinese herbal medicine in abrogating the constitutive STAT3 activation in human pancreatic tumor cells. METHODS The effect of morusin on STAT3 activation, associated protein kinases, STAT3-regulated gene products, cellular proliferation, and apoptosis was examined. RESULTS Morusin specifically inhibited constitutive STAT3 activation both at tyrosine residue 705 and serine residue 727 in 4 pancreatic tumor cells. The inhibition of STAT3 was mediated through the suppression of activation of upstream JAK1, JAK2, and c-Src kinases. Morusin led to the accumulation of the cells in different phases of the cell cycle and caused induction of apoptosis and loss of mitochondrial membrane potential. Morusin downregulated the expression of various STAT3-regulated gene products; this correlated with induction of caspase-3 activation and anti-invasive effects. Treatment with the protein tyrosine phosphatase inhibitor pervanadate reversed the morusin-induced downregulation of STAT3, thereby suggesting the involvement of a protein tyrosine phosphatase. CONCLUSIONS Morusin is a novel blocker of STAT3 activation and thus may have potential in negative regulation of growth and metastasis of pancreatic tumor cells.
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Lu H, Wang J, Wang Y, Qiao L, Zhou Y. Embelin and Its Role in Chronic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016:397-418. [DOI: 10.1007/978-3-319-41334-1_16] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Vohidov F, Knudsen SE, Leonard PG, Ohata J, Wheadon MJ, Popp BV, Ladbury JE, Ball ZT. Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors. Chem Sci 2015; 6:4778-4783. [PMID: 29142714 PMCID: PMC5667506 DOI: 10.1039/c5sc01602a] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Accepted: 06/03/2015] [Indexed: 01/23/2023] Open
Abstract
Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ∼ 200 nM).
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Affiliation(s)
- Farrukh Vohidov
- Department of Chemistry , Rice University , 6100 Main St. , Houston , Texas , USA .
| | - Sarah E Knudsen
- Department of Chemistry , Rice University , 6100 Main St. , Houston , Texas , USA .
| | - Paul G Leonard
- Department of Genomic Medicine , Core for Biomolecular Structure and Function , University of Texas , M.D. Anderson Cancer Center , Houston , Texas , USA
| | - Jun Ohata
- Department of Chemistry , Rice University , 6100 Main St. , Houston , Texas , USA .
| | - Michael J Wheadon
- Department of Chemistry , Rice University , 6100 Main St. , Houston , Texas , USA .
| | - Brian V Popp
- Eugene Bennett Department of Chemistry , West Virginia University , 217 Clark Hall , Morgantown , West Virginia , USA
| | - John E Ladbury
- Department of Molecular and Cellular Biology , University of Leeds , LS2 9JT , UK
| | - Zachary T Ball
- Department of Chemistry , Rice University , 6100 Main St. , Houston , Texas , USA .
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Lee JH, Kim C, Kim SH, Sethi G, Ahn KS. Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway. Cancer Lett 2015; 360:280-93. [DOI: 10.1016/j.canlet.2015.02.024] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 01/30/2015] [Accepted: 02/12/2015] [Indexed: 01/08/2023]
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Perisé-Barrios AJ, Gómez R, Corbí AL, de la Mata J, Domínguez-Soto A, Muñoz-Fernandez MA. Use of carbosilane dendrimer to switch macrophage polarization for the acquisition of antitumor functions. NANOSCALE 2015; 7:3857-3866. [PMID: 25254497 DOI: 10.1039/c4nr04038d] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Tumor microenvironment favors the escape from immunosurveillance by promoting immunosuppression and blunting pro-inflammatory responses. Since most tumor-associated macrophages (TAM) exhibit an M2-like tumor cell growth promoting polarization, we have studied the role of 2G-03NN24 carbosilane dendrimer in M2 macrophage polarization to evaluate the potential application of dendrimers in tumor immunotherapy. We found that the 2G-03NN24 dendrimer decreases LPS-induced IL-10 production from in vitro generated monocyte-derived M2 macrophages, and also switches their gene expression profile towards the acquisition of M1 polarization markers (INHBA, SERPINE1, FLT1, EGLN3 and ALDH1A2) and the loss of M2 polarization-associated markers (EMR1, IGF1, FOLR2 and SLC40A1). Furthermore, 2G-03NN24 dendrimer decreases STAT3 activation. Our results indicate that the 2G-03NN24 dendrimer can be a useful tool for antitumor therapy by virtue of its potential ability to limit the M2-like polarization of TAM.
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Affiliation(s)
- Ana J Perisé-Barrios
- Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón, 28007 Madrid, Spain.
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Kim MB, Kim C, Chung WS, Cho JH, Nam D, Kim SH, Ahn KS. The Hydrolysed Products of Iridoid Glycosides Can Enhance Imatinib Mesylate-Induced Apoptosis in Human Myeloid Leukaemia Cells. Phytother Res 2015; 29:434-43. [DOI: 10.1002/ptr.5272] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 10/31/2014] [Accepted: 11/25/2014] [Indexed: 12/12/2022]
Affiliation(s)
- Min-Beom Kim
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Chulwon Kim
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Won-Seok Chung
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Jae-Heung Cho
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Dongwoo Nam
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Sung-Hoon Kim
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
| | - Kwang Seok Ahn
- College of Korean Medicine; Kyung Hee University; 1 Hoegidong Dongdaemungu Seoul 130-701 Korea
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50
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Bocchini CE, Kasembeli MM, Roh SH, Tweardy DJ. Contribution of chaperones to STAT pathway signaling. JAKSTAT 2014; 3:e970459. [PMID: 26413421 DOI: 10.4161/21623988.2014.970459] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 09/21/2014] [Accepted: 09/25/2014] [Indexed: 12/27/2022] Open
Abstract
Aberrant STAT signaling is associated with the development and progression of many cancers and immune related diseases. Recent findings demonstrate that proteostasis modulators under clinical investigation for cancer therapy have a significant impact on STAT signaling, which may be critical for mediating their anti-cancer effects. Chaperones are critical for protein folding, stability and function and, thus, play an essential role in the maintenance of proteostasis. In this review we discuss the role of chaperones in STAT and tyrosine kinase (TK) protein folding, modulation of STAT and TK activity, and degradation of TKs. We highlight the important role of chaperones in STAT signaling, and how this knowledge has provided a framework for the development of new therapeutic avenues of targeting STAT signaling related pathologies.
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Affiliation(s)
- Claire E Bocchini
- Section of Infectious Disease; Department of Pediatrics; Baylor College of Medicine ; Houston, TX USA
| | - Moses M Kasembeli
- Section of Infectious Disease; Department of Medicine; Baylor College of Medicine ; Houston, TX USA
| | - Soung-Hun Roh
- Department of Biochemistry & Molecular Biology; Baylor College of Medicine ; Houston, TX USA
| | - David J Tweardy
- Section of Infectious Disease; Department of Medicine; Baylor College of Medicine ; Houston, TX USA ; Department of Biochemistry & Molecular Biology; Baylor College of Medicine ; Houston, TX USA ; Department of Molecular & Cellular Biology; Baylor College of Medicine ; Houston, TX USA
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