Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization.
Sarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomeno...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4026528?pdf=render |
| _version_ | 1811265180916514816 |
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| author | Alessandra De Robertis Federica Mennillo Marco Rossi Silvia Valensin Patrizia Tunici Elisa Mori Nicola Caradonna Maurizio Varrone Massimiliano Salerno |
| author_facet | Alessandra De Robertis Federica Mennillo Marco Rossi Silvia Valensin Patrizia Tunici Elisa Mori Nicola Caradonna Maurizio Varrone Massimiliano Salerno |
| author_sort | Alessandra De Robertis |
| collection | DOAJ |
| description | Sarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomenon, mainly accomplished by autocrine loop activity, is sustained by gene amplification, over-expression of Wnt ligands and co-receptors or epigenetic silencing of endogenous Wnt antagonists. We previously showed that pharmacological inhibition of Wnt signaling mediated by Axin stabilization produced in vitro and in vivo antitumor activity in glioblastoma tumors. Here, we report that targeting different sarcoma cell lines with the Wnt inhibitor/Axin stabilizer SEN461 produces a less transformed phenotype, as supported by modulation of anchorage-independent growth in vitro. At the molecular level, SEN461 treatment enhanced the stability of the scaffold protein Axin1, a key negative regulator of the Wnt signaling with tumor suppressor function, resulting in downstream effects coherent with inhibition of canonical Wnt signaling. Genetic phenocopy of small molecule Axin stabilization, through Axin1 over-expression, coherently resulted in strong impairment of soft-agar growth. Importantly, sarcoma growth inhibition through pharmacological Axin stabilization was also observed in a xenograft model in vivo in female CD-1 nude mice. Our findings suggest the usefulness of Wnt inhibitors with Axin stabilization activity as a potentialyl clinical relevant strategy for certain types of sarcomas. |
| first_indexed | 2024-04-12T20:18:59Z |
| format | Article |
| id | doaj.art-2121e44582214067a9f4b4269f7ca353 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T20:18:59Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2121e44582214067a9f4b4269f7ca3532022-12-22T03:18:03ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9784710.1371/journal.pone.0097847Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization.Alessandra De RobertisFederica MennilloMarco RossiSilvia ValensinPatrizia TuniciElisa MoriNicola CaradonnaMaurizio VarroneMassimiliano SalernoSarcomas are mesenchymal tumors showing high molecular heterogeneity, reflected at the histological level by the existence of more than fifty different subtypes. Genetic and epigenetic evidences link aberrant activation of the Wnt signaling to growth and progression of human sarcomas. This phenomenon, mainly accomplished by autocrine loop activity, is sustained by gene amplification, over-expression of Wnt ligands and co-receptors or epigenetic silencing of endogenous Wnt antagonists. We previously showed that pharmacological inhibition of Wnt signaling mediated by Axin stabilization produced in vitro and in vivo antitumor activity in glioblastoma tumors. Here, we report that targeting different sarcoma cell lines with the Wnt inhibitor/Axin stabilizer SEN461 produces a less transformed phenotype, as supported by modulation of anchorage-independent growth in vitro. At the molecular level, SEN461 treatment enhanced the stability of the scaffold protein Axin1, a key negative regulator of the Wnt signaling with tumor suppressor function, resulting in downstream effects coherent with inhibition of canonical Wnt signaling. Genetic phenocopy of small molecule Axin stabilization, through Axin1 over-expression, coherently resulted in strong impairment of soft-agar growth. Importantly, sarcoma growth inhibition through pharmacological Axin stabilization was also observed in a xenograft model in vivo in female CD-1 nude mice. Our findings suggest the usefulness of Wnt inhibitors with Axin stabilization activity as a potentialyl clinical relevant strategy for certain types of sarcomas.http://europepmc.org/articles/PMC4026528?pdf=render |
| spellingShingle | Alessandra De Robertis Federica Mennillo Marco Rossi Silvia Valensin Patrizia Tunici Elisa Mori Nicola Caradonna Maurizio Varrone Massimiliano Salerno Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. PLoS ONE |
| title | Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. |
| title_full | Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. |
| title_fullStr | Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. |
| title_full_unstemmed | Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. |
| title_short | Human Sarcoma growth is sensitive to small-molecule mediated AXIN stabilization. |
| title_sort | human sarcoma growth is sensitive to small molecule mediated axin stabilization |
| url | http://europepmc.org/articles/PMC4026528?pdf=render |
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