Areca (betel) nut extract activates mitogen‐activated protein kinasesand NF‐κB in oral keratinocytes

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Abstract
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‐κB, 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‐κB pathway in a biphasic manner, particularly for SAS cells. NF‐κB was activated by ∼ 2‐ to 4‐fold at 0.5–1 hr and a plateau or slight decrease of activity existed between 1 and 6 hr. Later, another higher episode of NF‐κB activity was raised. This was accompanied with the rapid degradation in cytosolic IκBα as well as an increase of nuclear NF‐κB in both cells. ANE treatment did not activate epidermal growth factor receptor signaling system, but blockage of NF‐κB 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.