PLK4 inhibitor exhibits antitumor effect and synergizes sorafenib via arresting cell cycle and inactivating Wnt/β-catenin pathway in anaplastic thyroid cancer

Abstract

ABSTRACT The anti-tumor effect of polo-like kinase 4 (PLK4) inhibitor has been explored in several solid carcinomas, while its application in anaplastic thyroid cancer (ATC) remains scarce. Hence, the current study aimed to investigate the effect of PLK4 inhibitor on the malignant behaviors of ATC cell lines and its synergistic antitumor effect with sorafenib. C643 and 8305c cells were cultured in various concentrations of centrinone (PLK4 inhibitor) with or without sorafenib. Meanwhile, the cell viability, cell apoptosis, cell cycle and expressions of glycogen synthetase kinase beta (GSK3β), p-GSK3β, β-catenin were determined. PLK4 mRNA and protein expressions were higher in most ATC cell lines than the normal thyroid epithelial cell line (all P < .05). Centrinone decreased cell viability, induced cell apoptosis, arrested cell cycle at G2/M phase and inactivated Wnt/β-catenin signaling with dose-dependent manners in C643 and 8305c cells (all P < .05). Interestingly, centrinone plus sorafenib further improved antitumor effect (P < .05 at most concentrations), with the highest combination index at 5 nM centrinone plus 4 μM sorafenib in C643 cells, then 4 nM centrinone plus 4 μM sorafenib in C643 cells. Subsequently, centrinone plus sorafenib reduced cell viability, promoted cell apoptosis, facilitated cell cycle at G2/M phase and repressed Wnt/β-catenin signaling more effectively compared with centrinone or sorafenib monotherapy in C643 and 8305c cells (all P < .05). PLK4 inhibitor exhibits antitumor effect and synergizes sorafenib via arresting cell cycle and inactivating Wnt/β-catenin pathway in ATC.