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

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. © 2005 Wiley‐Liss, Inc.

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

“…2c). These results are consistent with previous reports 39, 43. Also, we confirmed that AN‐induced ROS generation was regulated through NF‐κB pathway, because the inhibitor of NF‐κB significantly attenuated ROS generation by AN‐extract (Fig.…”

Association of Expression Aberrances and Genetic Polymorphisms of Lysyl Oxidase with Areca-Associated Oral Tumorigenesis

“…ANE activates a range of signaling elements that underlie oral pathogenesis (1,2). The up-regulation of LOX mRNA expression in many NHOKs by ANE might create an advantage for oncogenesis.…”

“…Its high incidence in Southern Asians is due to the popularity of the habit of areca (betel) nut chewing (1). Areca nut extract was known to induce oncogenic signals in oral epithelial cells (1,2). Lysyl oxidase (LOX) is synthesized in cells as a preproenzyme.…”

Association between areca‐stimulated vimentin expression and the progression of head and neck cancers

“…Areca nut extract was also reported to upregulate COX-2 expression. 4,9 Areca nut extract-stimulated COX-2 and vimentin expression was mediated by ERK activation because pretreatment of cells with U0126 abrogated such expression in both OECM-1 ( Figure 1E) and OC3 cells ( Figure 1F). Cascade.…”

“…[4][5][6] OECM-1 is a moderately-differentiated HNSCC cell line cultivated in RPMI-1640 medium (Invitrogen, Carlsbad, CA). 4 OC3 was established in our laboratory from an areca nut chewer. It is a well-differentiated HNSCC cell line cultivated in a combined K-SFM-Dulbecco Modified Eagle's Medium (2:1, v/v, Invitrogen).…”