The tankyrase‐specific inhibitor JW74 affects cell cycle progression and induces apoptosis and differentiation in osteosarcoma cell lines

Abstract

Wnt/β-catenin is a major regulator of stem cell self-renewal and differentiation and this signaling pathway is aberrantly activated in a several cancers, including osteosarcoma (OS). Attenuation of Wnt/β-catenin activity by tankyrase inhibitors is an appealing strategy in treatment of OS. The efficacy of the tankyrase inhibitor JW74 was evaluated in three OS cell lines (KPD, U2OS, and SaOS-2) both at the molecular and functional level. At the molecular level, JW74 induces stabilization of AXIN2, a key component of the β-catenin destruction complex, resulting in reduced levels of nuclear β-catenin. At the functional level, JW74 induces reduced cell growth in all three tested cell lines, in part due to a delay in cell cycle progression and in part due to an induction of caspase-3-mediated apoptosis. Furthermore, JW74 induces differentiation in U2OS cells, which under standard conditions are resistant to osteogenic differentiation. JW74 also enhances differentiation of OS cell lines, which do not harbor a differentiation block. Interestingly, microRNAs (miRNAs) of the let-7 family, which are known tumor suppressors and inducers of differentiation, are significantly upregulated following treatment with JW74. We demonstrate for the first time that tankyrase inhibition triggers reduced cell growth and differentiation of OS cells. This may in part be due to an induction of let-7 miRNA. The presented data open for novel therapeutic strategies in the treatment of malignant OS.

Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells

“…In recent years, several efforts have been made in characterizing Wnt signaling status in sarcomas, but mostly focusing in specific sarcoma types, especially in osteosarcomas, in which the activation of the pathway is well established (27)(28)(29). Nevertheless, knowledge about this pathway in STS is still very limited.…”

Tankyrases: Structure, Function and Therapeutic Implications in Cancer

“…It has been proposed that the suppression of miRNA through Ago2, which is bound in SGs, may contribute to dynamic stress responses in cancer cells [ 133 , 149 ]. Interestingly, in the chondrosarcoma cell line U2OS, TNKS inhibitor reduced growth and induced differentiation accompanied by an increase of let-7 miRNA [ 150 ].…”

IGF-1/IGF-1R/hsa-let-7c axis regulates the committed differentiation of stem cells from apical papilla

“…MicroRNAs (miRNAs) are small RNA molecules and comprised of 21–25 nucleotides that modulate the inhibition of translation from mRNA to protein, promotion of mRNA degradation and control of gene transcription via binding to the 3′-untranslated region (UTR) of their target mRNAs12. The let-7 family of miRNAs is initially detected in caenorhabditis elegans and identified as a heterochronic gene, which is considered as a miRNA biomarker in osteoblastic and osteocytic differentiation of mesencymal stem cells1314.…”