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 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.
Molecular Oncology Unit, Siena Biotech Medicine Research Centre, Siena, Italy; Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy.
Alessandra
A
De Robertis
Molecular Oncology Unit, Siena Biotech Medicine Research Centre, Siena, Italy; Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy.
Federica
F
Mennillo
Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy; In Vivo Pharmacology Unit, Siena Biotech Medicine Research Centre, Siena, Italy.
Marco
M
Rossi
Molecular Oncology Unit, Siena Biotech Medicine Research Centre, Siena, Italy; Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy.
Silvia
S
Valensin
Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy; In Vivo Pharmacology Unit, Siena Biotech Medicine Research Centre, Siena, Italy.
Patrizia
P
Tunici
Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy; Data Analysis Unit, Siena Biotech Medicine Research Centre, Siena, Italy.
Elisa
E
Mori
MET Profiling Unit, Siena Biotech Medicine Research Centre, Siena, Italy.
Nicola
N
Caradonna
Department of Medicinal Chemistry, Siena Biotech Medicine Research Centre, Siena, Italy.
Maurizio
M
Varrone
Molecular Oncology Unit, Siena Biotech Medicine Research Centre, Siena, Italy; Department of Pharmacology, Siena Biotech Medicine Research Centre, Siena, Italy.
Massimiliano
M
Salerno
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D060466:Axin Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D016086:Lentivirus; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010957:Plasmids / Q000235:genetics; D055550:Protein Stability / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy / Q000503:physiopathology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
D000970:Antineoplastic Agents; D060466:Axin Protein; D017931:DNA Primers