Areca (betel) nut extract activates mitogen-activated protein kinases and NF-κB in oral keratinocytes

Areca (betel) was recently proved a carcinogenic substance by the International Agency for Research on Cancer. However, the Signaling impact of areca in oral keratinocyte is still obscure. Mitogen-activated protein kinase superfamilies, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38, together with transcription factor NF-kappa B, are important signaling elements. We examined the activation of these signaling pathways in OECM-1 and SAS oral keratinocytes, treated with ripe areca nut extract (ANE). In both cells, a rapid increase in JNK1 activity at 0.5 hr was noted following treatment of ANE. ERK was profoundly activated during 0.5-2 hr in OECM-1 cells. Contrasting p38 activity was noted in these 2 cells. In both cells, ANE also activated NF-kappa B pathway in a biphasic manner, particularly for SAS cells. NF-kappa B was activated by similar to 2- to 4-fold at 0.5-1 hr and a plateau or slight decrease of activity existed between I and 6 hr. Later, another higher episode of NF-kappa B activity was raised. This was accompanied with the rapid degradation in cytosolic I kappa B alpha as well as an increase of nuclear NF-kappa B in both cells. ANE treatment did not activate epidermal growth factor receptor signaling system, but blockage of NF-kappa B activation rendered the suppression of ANE-modulated COX-2 upregulation in OECM-1. This study identified that ANE affected interactive signaling systems in oral keratonocytes that could be the pathogenetic basis for areca. (c) 2005 Wiley-Liss, Inc.