T-LAK cell-originated protein kinase (TOPK) is a Novel Prognostic and Therapeutic Target in Chordoma.

Abstract

OBJECTIVES:

To assess the expression, prognostic value, and functionality of T-lymphokine-activated killer (T-LAK) cell-originated protein kinase (TOPK) in chordoma pathogenesis.

MATERIALS AND METHODS:

TOPK expression in chordoma was assessed via immunohistochemical staining of a tissue microarray (TMA) and correlated with patient clinicopathology. TOPK expression in chordoma cell lines and fresh patient tissues was then evaluated by Western blot. TOPK small interfering RNA (siRNA) and the specific inhibitor OTS514 were applied to determine the roles of TOPK in chordoma pathogenicity. The effect of TOPK expression on chordoma cell clonogenicity was also investigated using clonogenic assays. A 3D cell culture model was utilized to mimic in vivo environment to validate the effect of TOPK inhibition on chordoma cells.

RESULTS:

TOPK was highly expressed in 78.2% of the chordoma specimens in the TMA and all chordoma cell lines. High TOPK expression significantly correlated with metastasis, recurrence, disease status and shorter overall survival. Knockdown of TOPK with specific siRNA resulted in significantly decrease chordoma cell viability. Inhibition of TOPK with OTS514 significantly inhibited chordoma cell growth and proliferation, colony-forming capacity and ex vivo spheroid growth.

CONCLUSIONS:

High expression of TOPK is an important predictor of poor prognosis in chordoma. Inhibition of TOPK resulted in significantly decrease chordoma cell proliferation and increase apoptosis. Our results indicate TOPK as a novel prognostic biomarker and therapeutic target for chordoma.

• Authors: Pichaya Thanindratarn, Dylan C Dean, Scott D Nelson, Francis J Hornicek, Zhenfeng Duan
• Journal: Cell proliferation (Cell Prolif) Vol. 53 Issue 10 Pg. e12901 (Oct 2020) ISSN: 1365-2184 [Electronic] England
• PMID: 32960500 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.

Chemical References

• OTS514
• Protein Kinase Inhibitors
• Quinolones
• RNA, Small Interfering
• Thiophenes
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Bone Neoplasms (metabolism, mortality, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chordoma (metabolism, mortality, pathology)
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Metastasis
• Prognosis
• Protein Kinase Inhibitors (pharmacology)
• Quinolones (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Thiophenes (pharmacology)