Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines

Abstract

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.

Effect of the PARP inhibitor veliparib on germ cell tumor cell lines

“…Model GCT cell line selected for the study. Five GCT cell lines and their cisplatin-resistant variants, which have been previously characterized (33)(34)(35), were used in this study. NTERA-2 and NCCIT represent pluripotent embryonal carcinoma (EC) cell lines, JEG-3 is a choriocarcinoma (ChC) cell line, and NOY-1 was derived from ovarian yolk sac tumor (YST).…”

“…ENG101, FA; Kerafast) cell lines were cultivated in RPMI (GIBCO ® Invitrogen) containing 10% FBS, 10.000 IU/ml penicillin, 5 µg/ml streptomycin, 2.5 µg/ml amphotericin and 2 mM glutamine. Cisplatin-resistant variants of parental cell lines, designated CisR, were all derived by propagating the cells in increasing concentrations of cisplatin (Hospira UK Ltd.) for 6 months as described previously (33)(34)(35). All cell lines were cultivated at 37˚C in a humidified atmosphere and 5% CO 2 .…”

Prognostic role of plasma vitamin D and its association with disease characteristics in germ cell tumours

“…Moreover, hypoxemia-induced factor 1-a (HIF-1a) is also affected by vitamin D, which plays a role in epithelial–mesenchymal transmission, migrations and has an impact on vascular proliferation ( 41 ); however, no study addressing the role of vitamin D and HIF-1a in germ cell tumors currently exists. Another significant role of vitamin D is the mediation of inhibition via the Wnt/β-catenin pathway ( 61 ), while it is already known that high β-catenin levels are associated with poor clinico-pathological features in germ cell tumors ( 62 , 63 ). Another possible conjunction of vitamin D and progressive disease might be due to low expression of MAPKAPK2, which is already known to play a role in cancer invasion ( 64 , 65 ).…”

WNT Signaling as a Therapeutic Target for Glioblastoma

“…PRI-724 potently disrupts β-catenin interaction with CBP, thereby inhibiting acute myeloid leukemia (AML) cells and synergizing with FLT3 inhibition in FLT3-mutant AML [116]. It also showed anti-cancer effects in testicular germ cell tumors and human osteosarcoma cells [117,118]. A recent study revealed that PRI-724 is a potent antifibrotic agent in the lungs [119].…”