Casein kinase 2 inhibitor CX-4945 elicits an anti-Warburg effects through the downregulation of TAp73 and inhibits gastric tumorigenesis.

Abstract

Casein kinase 2 (CK2) has become a potential therapeutic target in gastric cancer; however, the underlying mechanism remains incompletely understood. TAp73, a structural homolog of the tumor suppressor p53, acts as a critical regulator of the Warburg effect. Recent study reveals that aberrant CK2 signaling is able to inhibit TAp73 function. Here we determine that TAp73 is overexpressed in AGS-1 but not in SNU-5 gastric cancer cell line as compared with normal gastric cells. In addition, we show that TAp73 expression is required for the maintenance of glucose uptake and lactate release in AGS-1 but not in SNU-5 gastric cancer cells. Importantly, the use of CX-4945, a selective inhibitor of protein kinase CK2, inhibits cell growth and invasion, and promotes cell apoptosis in AGS-1 with decreased TAp73 expression as well as downregulated glucose uptake and lactate release. Although TAp73 knockdown resulted in significant decreases in TAp73 expressions in SNU-5 cell line, no differences in glucose uptake and lactate release were observed between SNU-5 and normal gastric cells. Moreover, TAp73 gene overexpression promotes glucose uptake and lactate release and abolishes the anti-cancer effects of CX-4945 in gastric cancer cell line AGS-1. The impacts of CX-4945 on glycolysis and tumorigenesis were strongly limited in SNU-5 gastric cancer cell line. These findings suggest that CX-4945 elicits an anti-Warburg effects in gastric cancer overexpressing Tap73 and inhibits gastric tumorigenesis.

• Authors: Shengli Tang, Yufeng Yuan, Zhisu Liu, Yueming He, Dingyu Pan
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 530 Issue 4 Pg. 686-691 (10 01 2020) ISSN: 1090-2104 [Electronic] United States
• PMID: 32771361 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Naphthyridines
• Phenazines
• Protein Kinase Inhibitors
• Tumor Protein p73
• silmitasertib
• Casein Kinase II

Topics

• Anticarcinogenic Agents (pharmacology)
• Carcinogenesis (drug effects)
• Casein Kinase II (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Humans
• Naphthyridines (pharmacology)
• Phenazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Stomach Neoplasms (genetics, metabolism, prevention & control)
• Tumor Protein p73 (genetics, metabolism)
• Warburg Effect, Oncologic (drug effects)