Sorafenib downregulates ERK/Akt and STAT3 survival pathways and induces apoptosis in a human neuroblastoma cell line

International Journal of Clinical and Experimental Pathology

Priya Weerasinghe¹  Hong Chai¹  Annie Z Luo¹  Robert E Brown¹ 

关键词: Neuroblastoma;    Sorafenib;    Apoptosis;    Akt1/2/3 Protein Kinase;    Signal Transducer and Activator of Transcription 3;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Neuroblastoma is a common solid tumor in children and its tumorigenicity is enhanced by the expression of survival pathways such as Akt and signal transducer and activator of transcription 3 (STAT3). Sorafenib is a multikinase inhibitor that also inhibits STAT3 signaling and induces apoptosis. In this study, we will examine the efficacy of sorafenib on a human neuroblastoma cell line (SK-N-AS) and also investigate its possible mechanisms. After cells reached 50-60% confluence, they were treated with various concentrations of sorafenib (0, 0.1, 1, 5, 10 and 20 μM) for different periods of time. The cell viability and apoptosis were determined by MTS colorimetric assay and TUNEL, respectively. Phosphorylation of Akt1/2/3 (p-Akt1/2/3), extracellular signal-regulated kinase 1/2 (p-ERK1/2), STAT3 (p-STAT3), and AMP-activated protein kinase alpha subunit (p-AMPKα) were determined with Western blot. The results indicate that as early as 2 hours post-treatment, cell viability was significantly decreased at 10 μM concentration. In 24 hours or longer treatment groups, sorafenib at 5 μM and above significantly decreased cell viability. TUNEL assay showed a significant increased of apoptosis in 5 and 20 μM treatment groups 24 hours after treatment. Western blots showed a decrease of p-ERK1/2, p-Akt1/2/3, p-STAT3, and p-AMPKα expression levels in various sorafenib treatment groups. Our results indicate that sorafenib significantly decreased cell viability and increased apoptosis in human neuroblastoma cell line in association with down-regulation of p-ERK1/2, p-Akt, p-STAT3 survival pathways. These data suggested potential clinical application of sorafenib in the treatment of neuroblastoma.

【 授权许可】

Unknown