The Induction of Prostaglandin E2 Production, Interleukin-6 Production, Cell Cycle Arrest, and Cytotoxicity in Primary Oral Keratinocytes and KB Cancer Cells by Areca Nut Ingredients Is Differentially Regulated by MEK/ERK Activation

Chang, Mei‐Chi; Wu, Hui‐Lin; Lee, Jang‐Jaer; Lee, Po-Hsuen; Chang, Hung‐Hao; Hahn, Liang‐Jiunn; Lin, Bor-Ryu; Chen, Yi-Jane; Jeng, Jiiang‐Huei

doi:10.1074/jbc.m404465200

Cited by 120 publications

(149 citation statements)

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“…The findings were also in agreement with a report describing that 100-800 lg/ml tender ANE stimulate ERK in a keratinocyte. 30 However, ERK was not activated in SAS cells. In fact, ERK2 and ERK can be constitutively repressed during the late time courses in both cells.…”

Section: Discussionmentioning

confidence: 98%

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

Lin

Lee

et al. 2005

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 98%

“…2,30 Evidences indicated that ANE was a stress inducer. [7][8][9] A low concentration of ANE was used in this study to dissect the signaling responses relevant to the chronic oral exposure in target cells.…”

Section: Discussionmentioning

confidence: 99%

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

Lin

Lee

et al. 2005

Intl Journal of Cancer

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“…Data suggest that COX-2 may also be required for brain muscarinic signaling. In this regard, COX-2 deficient mice do not show any increase in AA incorporation in response to arecoline (Basselin, personal communication), and activation of muscarinic receptors by arecoline coupled to cPLA 2 [3,22,23] leads to increased generation of PGE 2 [16]. Indeed, evidence suggests that certain aspects of brain cholinergic function are diminished with advancing age [34].…”

Section: Discussionmentioning

confidence: 99%

Regional protein levels of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey brain as a function of age

Weerasinghe

Coon

Bhattacharjee

et al. 2006

Brain Research Bulletin

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Limited evidence suggests that brain cytosolic phospholipase A 2 (cPLA 2 ), which selectively releases arachidonic acid (AA) from membrane phospholipids, and cyclooxygenase-2 (COX-2), the ratelimiting enzyme for AA metabolism to prostanoids, change as a function of normal aging. In this study, we examined the protein levels of cPLA 2 and COX-2 enzymes in hippocampus, frontal pole and cerebellum from young (2-5 year-old), middle-aged (8-11 year-old) and old (23 year-old) male and female Rhesus monkeys. In the cerebellum, cPLA 2 protein level was higher in the young brain as compared to levels seen at both middle-aged and old. Similarly, in the frontal pole, the young brain showed a higher level of COX-2 protein as compared to the levels seen at both older ages. For both, once an animal reached 8-11 years of age the levels appeared to remain relatively constant over the next decade. Immunohistochemistry of COX-2 protein within the brain demonstrated no significant change in the localization to neurons within the frontal pole. In the young brain, the distribution of a low level of COX-2 protein within numerous neurons was different than the decreased number of neurons stained at a greater intensity in the adult brain. Based on the previous reports of localization of cPLA 2 and COX-2 at post-synaptic sites in neurons results from the current study suggest that the elevated protein levels of the two enzymes seen in the younger brain is related to the greater potential for synaptic plasticity across multiple neurons as a function of age and that cPLA 2 and COX-2 may be considered as post-synaptic markers.

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“…Betel quid usually comprises a piece of areca nut, which contains many polyphenols and several alkaloids, Piper betle, and lime with or without Piper betle leaves [6] . Arecoline, a major component of areca nut can produce 3-methyl nitrosamine propionitrile (MNPN), a potent carcinogen and safrolelike DNA adducts that have been shown to be genotoxic and mutagenic.…”

Section: Gene Expression Profile Of Esophageal Cancer In North Eastmentioning

confidence: 99%

Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis

Chattopadhyay

Kapur²,

Purkayastha³

et al. 2007

WJG

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AIM:To identify alterations in genes and molecular functional pathways in esophageal cancer in a high incidence region of India where there is a widespread use of tobacco and betel quid with fermented areca nuts. METHODS:Total RNA was isolated from tumor and matched normal tissue of 16 patients with esophageal squamous cell carcinoma. Pooled tumor tissue RNA was labeled with Cy3-dUTP and pooled normal tissue RNA was labeled with Cy5-dUTP by direct labeling method. The labeled probes were hybridized with human 10K cDNA chip and expression profiles were analyzed by Genespring GX V 7.3 (Silicon Genetics). RESULTS:Nine hundred twenty three genes were differentially expressed. Of these, 611 genes were upregulated and 312 genes were downregulated. Using stringent criteria (P ≤ 0.05 and ≥ 1.5 fold change), 127 differentially expressed genes (87 upregulated and 40 downregulated) were identified in tumor tissue. On the basis of Gene Ontology, four different m o l e c u l a r fu n c t i o n a l p a t hway s ( M A P K p a t hway, G-protein coupled receptor family, ion transport activity, and serine or threonine kinase activity) were most significantly upregulated and six different molecular functional pathways (structural constituent of ribosome, endopeptidase inhibitor activity, structural constituent of cytoskeleton, antioxidant activity, acyl group transferase activity, eukaryotic translation elongation factor activity)

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The Induction of Prostaglandin E2 Production, Interleukin-6 Production, Cell Cycle Arrest, and Cytotoxicity in Primary Oral Keratinocytes and KB Cancer Cells by Areca Nut Ingredients Is Differentially Regulated by MEK/ERK Activation

Cited by 120 publications

References 47 publications

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

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

Regional protein levels of cytosolic phospholipase A2 and cyclooxygenase-2 in Rhesus monkey brain as a function of age

Gene expression profile of esophageal cancer in North East India by cDNA microarray analysis

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