CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1 alpha in Hepatoma Cells

Abstract

In rapidly growing tumors, hypoxia commonly develops due to the imbalance between O(2) consumption and supply Hypoxia Inducible Factor (HIF)-1 alpha is a transcription factor responsible for tumor growth and angiogenesis in the hypoxic microenvironment, thus, its inhibition is regarded as a promising strategy for cancer therapy Given that CamKII or PARP inhibitors are emerging anticancer agents, we investigated if they have the potential to be developed as new HIF-1 alpha-targeting drugs When treating various cancer cells with the inhibitors, we found that a CamKII inhibitor, KN-62, effectively suppressed HIF-1 alpha specifically in hepatoma cells To examine the effect of KN-62 on HIF-1 alpha-driven gene expression, we analyzed the EPO-enhancer reporter activity and mRNA levels of HIF-1 alpha downstream genes, such as EPO, LOX and CA9 Both the reporter activity and the mRNA expression were repressed by KN-62 We also found that KN-62 suppressed HIF-1 alpha by impairing synthesis of HIF-1 alpha protein Based on these results, we propose that KN-62 is a candidate as a HIF-1 alpha-targeting anticancer agent