Areca nut extract upregulates vimentin by activating PI3K/AKT signaling in oral carcinoma.
BACKGROUND
Areca nut is a group I carcinogen. Areca nut extract (ANE) is known to activate signaling pathways in oral epithelial cells. Activation of the serine/threonine protein kinase AKT/pKB (AKT) signaling pathway is known to be important during the neoplastic process. Vimentin is a mesenchymal intermediate filament and a regulator of tumor progression. This study investigated the impact of ANE on PI3K/AKT activation during vimentin expression.


METHODS
Oral carcinoma cells were treated with ANE to explore the signaling changes underlying vimentin expression. Oral carcinoma tissues were subjected to immunohistochemical analysis to study the implications that vimentin expression has on patient survival.


RESULTS
After ANE treatment, the OECM-1 and Fadu cells developed a fibroblastoid morphology and there was an increase in vimentin expression. The treatment also induced the phosphorylation of AKT and glycogen synthase kinase 3β in OECM-1 cells. Blockage of phosphatidylinositol 3-kinase (PI3K)/AKT signaling attenuated vimentin expression when it was induced by ANE. However, it did not affect ANE-mediated extracellular signal-regulated kinase (ERK) activation or cyclooxygenase 2 (COX-2) upregulation. Oral carcinoma tissue samples were found to have significantly higher levels of vimentin and pAKT expression than their controls. Tumors exhibiting no vimentin expression and weak AKT phosphorylation were found to be associated with better survival than groups with high levels of expression.


CONCLUSIONS
Our results imply that PI3K/AKT activation and vimentin expression are important pathogenic cascades in areca-associated oral carcinogenesis.
Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
Yu-Hsin
YH
Tseng
Cheng-Chieh
CC
Yang
Shu-Chun
SC
Lin
Chia-Chen
CC
Cheng
Shu-Hui
SH
Lin
Chung-Ji
CJ
Liu
Kuo-Wei
KW
Chang
D001114:Areca; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor / Q000187:drug effects; D016009:Chi-Square Distribution; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality; D009754:Nuts; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation; D014746:Vimentin / Q000096:biosynthesis*
D010936:Plant Extracts; D014746:Vimentin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases