CDK5RAP3 acts as a putative tumor inhibitor in papillary thyroid carcinoma via modulation of Akt/GSK-3β/Wnt/β-catenin signaling

Abstract

Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) has been documented as a vital cancer-related protein that is implicated in numerous cancer types. However, the relevance of CDK5RAP3 in papillary thyroid carcinoma (PTC) is less well understood. The goal of this work was to understand the relationship between CDK5RAP3 and PTC. Our data showed significant decreases in CDK5RAP3 levels in PTC tissues and cell lines. Functional studies revealed that upregulation of CDK5RAP3 in PTC cell lines resulted in significant reduction of cellular proliferation. Moreover, overexpression of CDK5RAP3 induced apoptosis and cell cycle arrest in PTC cells. In addition, the migration, invasion and epithelial-mesenchymal transition in PTC cells were markedly suppressed via overexpression of CDK5RAP3. Further investigation documented that overexpression of CDK5RAP3 remarkably downregulated the levels of phospho-Akt, phospho-GSK-3β, and active β-catenin, leading to a significant decrease in activation of the Wnt/β-catenin pathway. Notably, knockdown of Akt abolished CDK5RAP3-silencing-mediated effects on the Wnt/β-catenin pathway. Reactivation of the Wnt/β-catenin pathway partially reversed CDK5RAP3-mediated tumor-inhibitory effects in PTC cells. Overexpression of CDK5RAP3 also weakened the tumorigenic potential of PTC cells in vivo. In summary, our work demonstrates that CDK5RAP3 is underexpressed in PTC and acts as a putative tumor suppressor of PTC. Our findings reveal that CDK5RAP3 exerts a tumor-suppressive role in PTC through downregulation of Wnt/β-catenin signaling via modulation of the Akt/GSK-3β axis.

Keywords: Akt; CDK5RAP3; Papillary thyroid carcinoma; Wnt.