Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells.

Abstract

T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.

• Authors: Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 14 Pg. 17652-64 (Apr 05 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26933922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXM1 protein, human
• Forkhead Box Protein M1
• Protein Kinase Inhibitors
• Small Molecule Libraries
• MELK protein, human
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation
• Forkhead Box Protein M1 (biosynthesis, genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Kidney Neoplasms (drug therapy, enzymology, pathology)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Molecular Targeted Therapy
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• Small Molecule Libraries (pharmacology)
• Transfection