FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases

Gustafson, Carl T.; Mamo, Tewodros; Shogren, Kristen L.; Maran, Avudaiappan; Yaszemski, Michael J.

doi:10.3389/fphar.2017.00285

Cited by 19 publications

(12 citation statements)

References 52 publications

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“…Therefore, the inhibition of the Wnt/β-catenin pathway can serve as a potential therapeutic approach for cancer (29–31). FH535 is an inhibitor of β-catenin, which inhibits cyclin D1 and survivin and decreases the proliferation of human colorectal cancer cells, liver cancer stem cells, hepatocellular carcinoma cells and HepG2 cells (24,32–34).…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA colon cancer‑associated transcript 2 may promote esophageal cancer growth and metastasis by regulating the Wnt signaling pathway

Wang

2019

Oncol Lett

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The aim of this study was to investigate how long non-coding (lnc)RNA colon cancer-associated transcript 2 (CCAT2) regulates the proliferation, invasion and metastasis of esophageal cancer cells via the Wnt signaling pathway. The expression of lncRNA CCAT2 was quantified by reverse transcription-quantitative PCR in four esophageal cancer cell lines (Eca-109, EC9706, KYSE150 and TE-1) and normal human esophageal epithelial cells (HEECs). The effect of silencing CCAT2 (si-CCAT2) and inhibiting Wnt signaling (using the inhibitor FH535) on the proliferation, migration and invasion of Eca-109 cells was measured by MTT, wound-healing and Transwell invasion assays. Flow cytometry was used to evaluate apoptosis in si-CCAT2 Eca-109 cells. The expression of β-catenin and proliferating cell nuclear antigen (PCNA) proteins was detected by immunohistochemistry. The pro-apoptotic protein Bax, cyclin D1 and Wnt target proteins, including c-Myc and adenomatous polyposis coli (APC), were detected by western blotting. LncRNA CCAT2 was highly expressed in the four esophageal cancer cell lines compared with the HEEC cells. The expression of CCAT2 was significantly decreased in si-CCAT2 Eca-109 cells. Treatment with si-CCAT2 and FH535 alone or in combination significantly inhibited the proliferation, migration and invasion of Eca-109 cells. The treatments also promoted apoptosis, upregulated the expression of Bax and APC proteins, and downregulated β-catenin, PCNA, cyclin D1 and c-Myc proteins. In summary, lncRNA CCAT2 is upregulated in esophageal cancer cells and the knockdown of lncRNA CCAT2 inhibits their proliferation, migration and invasion via the Wnt signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA colon cancer‑associated transcript 2 may promote esophageal cancer growth and metastasis by regulating the Wnt signaling pathway

Wang

2019

Oncol Lett

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“…We next investigated the effect of FH535, which is a synthetic small molecule that antagonizes the action of β-catenin/TCF/LEF transcription factors [ 37 , 65 ]. Our data suggest that FH535 attenuates β-catenin expression by 2-fold compared to untreated cells ( Figure 9E and 9F ).…”

Section: Resultsmentioning

confidence: 99%

Evidence for functional and regulatory cross-talk between Wnt/β-catenin signalling and Mre11-Rad50–Nbs1 complex in the repair of cisplatin-induced DNA cross-links

Pasadi

Muniyappa

2020

Oncotarget

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The canonical Wnt/β-catenin signalling pathway plays a crucial role in a variety of functions including cell proliferation and differentiation, tumorigenic processes and radioresistance in cancer cells. The Mre11–Rad50–Nbs1 (MRN) complex has a pivotal role in sensing and repairing DNA damage. However, it remains unclear whether a connection exists between Wnt/β-catenin signalling and the MRN complex in the repair of cisplatin-induced DNA interstrand cross-links (ICLs). Here, we report that (1) cisplatin exposure results in a significant increase in the levels of MRN complex subunits in human tumour cells; (2) cisplatin treatment stimulates Wnt/β-catenin signalling through increased β-catenin expression; (3) the functional perturbation of Wnt/β-catenin signalling results in aberrant cell cycle dynamics and the activation of DNA damage response and apoptosis; (4) a treatment with CHIR99021, a potent and selective GSK3β inhibitor, augments cisplatin-induced cell death in cancer cells. On the other hand, inactivation of the Wnt/β-catenin signalling with FH535 promotes cell survival. Consistently, the staining pattern of γH2AX-foci is significantly reduced in the cells exposed simultaneously to cisplatin and FH535; and (5) inhibition of Wnt/β-catenin signalling impedes cisplatin-induced phosphorylation of Chk1, abrogates the G2/M phase arrest and impairs recombination-based DNA repair. Our data further show that Wnt signalling positively regulates the expression of β-catenin, Mre11 and FANCD2 at early time points, but declining thereafter due to negative feedback regulation. These results support a model wherein Wnt/β-catenin signalling and MRN complex crosstalk during DNA ICL repair, thereby playing an important role in the maintenance of genome stability.

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“…In the wound healing experiment, the 20 µM concentration of FH535 significantly reduced migration at 8 and 12 hours [16]. Also, it has been reported that FH535 inhibits proliferation at concentrations of 0.1µM, 1µM, and 10µM in osteosarcoma cells [17]. The antiprolif-erative effect observed in hepatocellular carcinoma cells with the addition of FH535 at 50µM concentration is similar to our study, but the antiproliferative effect observed in colorectal cancer cells with the addition of FH535 at 10µM concentration was not noticed in HEC1A cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Wnt/β-catenin pathway inhibitors on cell proliferation and migration of HEC-1A endometrial adenocarcinoma: experimental cell culture model

Çirçirci

Tiftik

Ün

2021

The European Research Journal

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Objectives:The most diagnosed tumor among infiltrating tumors of the female genital tract is endometrial carcinoma. The Wnt/β-catenin signaling pathway has an important role in organogenesis, self-renewal of tissues, and adult stem cell maintenance. However aberrant activation of it causes many types of tumors and also related to the prognosis of patients. Therefore, we aimed to investigate whether Wnt/β-catenin pathway inhibitors have any effect on the proliferation and migration of tumor cells. Methods: As cancer cell line, HEC-1A endometrial adenocarcinoma was used. The Wnt/β-catenin pathway inhibitors effects on proliferation and migration were demonstrated by real-time cell analysis device and wound healing model respectively. Results: Wnt/β-catenin pathway inhibitors FH535 (25 μM at 36 th hour, p < 0.05; 50μM at 48 th hour p < 0.001) and niclosamide inhibited cell proliferation (10, 25 and 50μM at 60 th hours; p < 0.01, p < 0.05 and p < 0.001, respectively) whereas ICRT14 and IWP-2 did not. However only niclosamide which is also an antihelmintic drug inhibited migration of the cells in all concentrations tested (10, 25 and 50μM, p < 0.05). Conclusions:The present study shows that the Wnt/β-catenin pathway has an substantial role in both proliferation and migration of endometrial adenocarcinoma. We suggest that the antihelmintic drug niclosamide could be further investigated for its potential therapeutic effect in endometrial adenocarcinoma.

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FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases

Cited by 19 publications

References 52 publications

Long non‑coding RNA colon cancer‑associated transcript 2 may promote esophageal cancer growth and metastasis by regulating the Wnt signaling pathway

Long non‑coding RNA colon cancer‑associated transcript 2 may promote esophageal cancer growth and metastasis by regulating the Wnt signaling pathway

Evidence for functional and regulatory cross-talk between Wnt/β-catenin signalling and Mre11-Rad50–Nbs1 complex in the repair of cisplatin-induced DNA cross-links

Effect of the Wnt/β-catenin pathway inhibitors on cell proliferation and migration of HEC-1A endometrial adenocarcinoma: experimental cell culture model

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