Inhibition of casein kinase II reduces TGFβ induced fibroblast activation and ameliorates experimental fibrosis
Open accessAbstract
OBJECTIVES: Casein kinase II (CK2) is a constitutively active serine/threonine protein kinase that plays a key role in cellular transformation and tumorigenesis. The purpose of the study was to characterise whether CK2 contributes to the pathologic activation of fibroblasts in patients with SSc and to evaluate the antifibrotic potential of CK2 inhibition. METHODS: Activation of CK2, JAK2 and STAT3 in human skin and in experimental fibrosis was analysed by immunohistochemistry. CK2 signalling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGFβ receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo. RESULT: Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGFβ-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGFβ on collagen release and myofibroblasts differentiation in cultured fibroblasts. Inhibition of CK2 prevented bleomycin-induced and TBR-induced skin fibrosis with decreased dermal thickening, lower myofibroblast counts and reduced accumulation of collagen. Treatment with TBB also induced regression of pre-established fibrosis. The antifibrotic effects of TBB were accompanied by reduced activation of JAK2/STAT3 signalling in vivo. CONCLUSIONS: We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the pro-fibrotic effects of TGFβ and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.
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TGF-β1 signaling can induce STAT3-dependent fibrotic responses by phosphorylation and activation of JAK2.
“TGF-β1 signaling can induce STAT3-dependent fibrotic responses by phosphorylation and activation of JAK2”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Zhang et al., 2015
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β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis
Beyer, C., Schramm, A., Akhmetshina, A., Dees, C., Kireva, T., Gelse, K., Sonnylal, S., de Crombrugghe, B., Taketo, M. M., Distler, O., et al. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200568 · Cited by 203 · see citing works
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Research works printed but not linked: 37
- Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 2009;360:1989-2003.
- Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010;69:1809-15.
- Samarakoon R, Overstreet JM, Higgins PJ. TGF-beta signaling in tissue fibrosis: redox controls, target genes and therapeutic opportunities. Cell Signal 2013;25:264-8.
- Duncan JS, Litchfield DW. Too much of a good thing: the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta 2008;1784:33-47.
- Montenarh M. Cellular regulators of protein kinase CK2. Cell Tissue Res 2010;342:139-46.
- Landesman-Bollag E, Romieu-Mourez R, Song DH, et al. Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 2001;20:3247-57.
- Yenice S, Davis AT, Goueli SA, et al. Nuclear casein kinase 2 (CK-2) activity in human normal, benign hyperplastic, and cancerous prostate. Prostate 1994;24:11-16.
- Daya-Makin M, Sanghera JS, Mogentale TL, et al. Activation of a tumor-associated protein kinase ( p40TAK) and casein kinase 2 in human squamous cell carcinomas and adenocarcinomas of the lung. Cancer Res 1994;54:2262-8.
- Faust RA, Gapany M, Tristani P, et al. Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Lett 1996;101:31-5.
- Stalter G, Siemer S, Becht E, et al. Asymmetric expression of protein kinase CK2 subunits in human kidney tumors. Biochem Biophys Res Commun 1994;202: 141-7.
- Brown MS, Diallo OT, Hu M, et al. CK2 modulation of NF-kappaB, TP53, and the malignant phenotype in head and neck cancer by anti-CK2 oligonucleotides in vitro or in vivo via sub-50-nm nanocapsules. Clin Cancer Res 2010;16:2295-307.
- Siddiqui-Jain A, Drygin D, Streiner N, et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 2010;70:10288-98.
- Mazzorana M, Pinna LA, Battistutta R. A structural insight into CK2 inhibition. Mol Cell Biochem 2008;316:57-62.
- Zheng Y, Qin H, Frank SJ, et al. A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway. Blood 2011;118:156-66.
- Dees C, Tomcik M, Palumbo-Zerr K, et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor beta in systemic sclerosis. Arthritis Rheum 2012;64:3006-15.
- LeRoy EC, Medsger TA Jr. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573-6.
- Khodzhigorova A, Distler A, Lang V, et al. Inhibition of sumoylation prevents experimental fibrosis. Ann Rheum Dis 2012;71:1904-8.
- Akhmetshina A, Dees C, Pileckyte M, et al. Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. Arthritis Rheum 2008;58:2553-64.
- Distler JH, Jungel A, Huber LC, et al. The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cell microparticles. Proc Natl Acad Sci U S A 2005;102:2892-7.
- Dees C, Tomcik M, Zerr P, et al. Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 2011;70:1304-10.
- Reich N, Maurer B, Akhmetshina A, et al. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum 2010;62:280-90.
- Beyer C, Skapenko A, Distler A, et al. Activation of pregnane X receptor inhibits experimental dermal fibrosis. Ann Rheum Dis 2013;72:621-5.
- Reich N, Tomcik M, Zerr P, et al. Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis. Ann Rheum Dis 2012;71:737-45.
- Dees C, Akhmetshina A, Zerr P, et al. Platelet-derived serotonin links vascular disease and tissue fibrosis. J Exp Med 2011;208:961-72.
- Palumbo K, Zerr P, Tomcik M, et al. The transcription factor JunD mediates transforming growth factor {beta}-induced fibroblast activation and fibrosis in systemic sclerosis. Ann Rheum Dis 2011;70:1320-6.
- Avouac J, Furnrohr BG, Tomcik M, et al. Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum 2011;63:800-9.
- Avouac J, Palumbo K, Tomcik M, et al. Inhibition of activator protein 1 signaling abrogates transforming growth factor beta-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis Rheum 2012;64:1642-52.
- Beyer C, Schett G, Distler O, et al. Animal models of systemic sclerosis: prospects and limitations. Arthritis Rheum 2010;62:2831-44.
- Palumbo-Zerr K, Horn A, Distler A, et al. Inactivation of fatty acid amide hydrolase exacerbates experimental fibrosis by enhanced endocannabinoid-mediated activation of CB1. Ann Rheum Dis 2012;71:2051-4.
- Kramer M, Dees C, Huang J, et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis 2013;72:614-20.
- Horn A, Kireva T, Palumbo-Zerr K, et al. Inhibition of hedgehog signalling prevents experimental fibrosis and induces regression of established fibrosis. Ann Rheum Dis 2012;71:785-9.
- Weingartner S, Zerr P, Tomcik M, et al. Pomalidomide is effective for prevention and treatment of experimental skin fibrosis. Ann Rheum Dis 2012;71:1895-9.
- Akhmetshina A, Venalis P, Dees C, et al. Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum 2009;60:219-24.
- Akhmetshina A, Palumbo K, Dees C, et al. Activation of canonical Wnt signalling is required for TGF-beta-mediated fibrosis. Nat Commun 2012;3:735.
- Beyer C, Reich N, Schindler SC, et al. Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis 2012;71:1019-26.
- Song DH, Dominguez I, Mizuno J, et al. CK2 phosphorylation of the armadillo repeat region of beta-catenin potentiates Wnt signaling. J Biol Chem 2003;278:24018-25.
- Cozza G, Pinna LA, Moro S. Kinase CK2 inhibition: an update. Curr Med Chem 2013;20:671-93.
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Studies have shown that TGF-b1 signaling can induce STAT3-dependent fibrotic responses by phosphorylation and activation of JAK2 (Zhang et al., 2015).”
BackgroundHuang, J., Beyer, C., Palumbo-Zerr, K., Zhang, Y., Ramming, A., Distler, A., Gelse, K., Distler, O., Schett, G., Wollin, L., et al. (2016) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2014-207109 · Cited by 196 · see citing works
Self-citationThe JAK2 pathway is activated in idiopathic pulmonary fibrosis
Milara, J., Hernandez, G., Ballester, B., Morell, A., Roger, I., Montero, P., Escrivá, J., Lloris, J. M., Molina-Molina, M., Morcillo, E., et al. (2018) · Respiratory Research · doi:10.1186/s12931-018-0728-9 · Cited by 188 · see citing works
- Authors
- Zhang, Y., Dees, C., Beyer, C., Lin, N.-Y., Distler, A., Zerr, P., Palumbo, K., Susok, L., Kreuter, A., Distler, O., Schett, G., & Distler, J. H. W.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Ruhr University Bochum (DE)
- HELIOS St. Elisabeth Klinik Oberhausen (DE)
- University Hospital Zurich (CH)
- Corresponding author
- Distler, Jörg H W
- ORCID
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 74
- Issue
- 5
- Pages
- 936-943
- ISSN
- 0003-4967 (ISSN-L)
- OpenAlex
- W2102206799
- Cited by
- 64
- References
- 1
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 11 · 2023: 10 · 2022: 3 · 2021: 8 · 2020: 4 · 2019: 1 · 2018: 5 · 2017: 2 · 2016: 6 · 2015: 1 · 2014: 2
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- green
- open.fau.de
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- OPUS FAU (Kooperativer Bibliotheksverbund Berlin-Brandenburg (KOBV), on behalf of the Universitätsbibliothek Erlangen-Nürnberg) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Array BioPharma
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Rheumatology › Dupuytren's Contracture and Treatments
- Keywords
- casein kinase 2, systemic sclerosis, fibroblast activation, TGF-beta, JAK2/STAT3 signaling, antifibrotic therapy, bleomycin-induced fibrosis, TGF-beta type I receptor, myofibroblast differentiation, collagen deposition, skin fibrosis
- MeSH terms
- Adult, Aged, Animals, Disease Models, Animal, Female, Fibroblasts, Fibrosis, Humans, Male, Middle Aged, Scleroderma, Systemic, Skin, Triazoles, Signal Transduction, Transforming Growth Factor beta, Casein Kinase II, STAT3 Transcription Factor, Mice, Janus Kinase 2, Young Adult
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