Jun N-terminal Kinase: a potential target for the treatment of head and neck squamous cell carcinoma (HNSCC)

2564 Jun N-terminal Kinase (JNK) is a stress-activated protein kinase responsible for the phosphorylation of c-Jun, a component of the activator protein-1 (AP-1) transcription factor complex. Changes in JNK or AP-1 activity can potentially affect a range of processes that are important for tumor growth including cell proliferation and angiogenesis. This preclinical study was carried out to investigate whether JNK is a potential target for treating HNSCC. Initially, JNK activity was evaluated in twenty paired samples (tumor vs. adjacent normal) of human HNSCC. Increased JNK activity was observed in >90% of the tumor samples. Subsequently, a HNSCC (1483 cell line) xenograft model was used to evaluate the anti-tumor activity of SP600125, a selective inhibitor of JNK. Treatment of mice bearing HNSCC xenografts with SP600125 (50 mg/kg/day) resulted in >60% inhibition of tumor growth relative to vehicle-treated animals [p in vitro studies to characterize the growth inhibitory and anti-angiogenic effects of SP600125. Treatment with SP600125 led to both dose- and time-dependent growth inhibition of 1483 cells. Growth inhibition was a consequence of reduced DNA synthesis and slowing of cell cycle progression through the S and G2 phases. To define the anti-angiogenic effects of SP600125, both 1483 tumor cells and human endothelial cells were employed. Treatment of 1483 cells with SP600125 caused a dose-dependent reduction in the production of VEGF. Inhibition of JNK activity also inhibited human microvascular endothelial cell proliferation and impaired endothelial cell capillary tube formation. Thus, SP600125-mediated inhibition of JNK activity appears to suppress angiogenesis via effects on both tumor cells and endothelial cells. Taken together, the results of this study provide a strong rationale for evaluating whether selective inhibitors of JNK activity will have a role in the treatment of HNSCC.