CaMKII Inhibitor KN-62 Blunts Tumor Response to Hypoxia by Inhibiting HIF-1alpha in Hepatoma Cells
The Korean Journal of Physiology and Pharmacology
;
: 331-336, 2010.
Article
in English
| WPRIM
| ID: wpr-728363
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Transcription Factors
/
RNA, Messenger
/
Gene Expression
/
Carcinoma, Hepatocellular
/
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
/
Calcium-Calmodulin-Dependent Protein Kinase Type 2
/
Hypoxia
/
Antineoplastic Agents
Language:
English
Journal:
The Korean Journal of Physiology and Pharmacology
Year:
2010
Type:
Article
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