CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1alpha in Hepatoma Cells.
10.4196/kjpp.2010.14.5.331
- Author:
Kyoung Hwa LEE
1
Author Information
1. Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Korea. lee12042@snu.ac.kr
- Publication Type:Original Article
- Keywords:
CaMKII;
HIF1-alpha;
Hepatocellular carcinoma;
Hypoxia;
KN-62
- MeSH:
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine;
Anoxia;
Antineoplastic Agents;
Calcium-Calmodulin-Dependent Protein Kinase Type 2;
Carcinoma, Hepatocellular;
Gene Expression;
RNA, Messenger;
Transcription Factors
- From:The Korean Journal of Physiology and Pharmacology
2010;14(5):331-336
- CountryRepublic of Korea
- Language:English
-
Abstract:
In rapidly growing tumors, hypoxia commonly develops due to the imbalance between O2 consumption and supply. Hypoxia Inducible Factor (HIF)-1alpha 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-1alpha-targeting drugs. When treating various cancer cells with the inhibitors, we found that a CamKII inhibitor, KN-62, effectively suppressed HIF-1alpha specifically in hepatoma cells. To examine the effect of KN-62 on HIF-1alpha-driven gene expression, we analyzed the EPO-enhancer reporter activity and mRNA levels of HIF-1alpha 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-1alpha by impairing synthesis of HIF-1alpha protein. Based on these results, we propose that KN-62 is a candidate as a HIF-1alpha-targeting anticancer agent.
