Gamma-secretase inhibitors exerts antitumor activity via down-regulation of Notch and Nuclear factor kappa B in human tongue carcinoma cells.
OBJECTIVE
To investigate the effect of the gamma-secretase inhibitors (GSIs) on the growth of human tongue carcinoma cells and to provide the molecular mechanism for potential application of GSIs in the treatment of tongue carcinoma.


METHODS
Human tongue carcinoma Tca8113 cells were cultured with the GSI L-685 458. Cell growth was determined by the methylthiazole tetrazolium method. Cell cycle and apoptosis were analyzed by flow cytometry and/or confocal microscopy. RT-PCR and Western blot were employed to determine the intracellular expression levels. Nuclear factor kappa B (NF-kappaB) activation was examined by electrophoretic mobility shift assay.


RESULTS
L-685,458 dose-dependently inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0-G1 cell cycle arrest and apoptosis. The mRNA and protein levels of Hairy/Enhancer of Split-1, a target of Notch activation, were decreased dose-dependently by L-685,458. Furthermore, L-685,458 down-regulated cyclin D1, B-cell lymphocytic-leukemia proto-oncogene 2 and c-Myc expressions, which are regulated by the transcription factor NF-kappaB. Coincident with this observation, L-685,458 induced a dose-dependent reduction of constitutive NF-kappaB activation in Tca8113 cells.


CONCLUSIONS
The GSI L-685,458 may have a therapeutic value for the treatment of human tongue carcinoma. Moreover, the effects of L-685,458 in tumor inhibition may act partially via the modulation of Notch and NF-kappaB.
Yao
J
J
School of Medicine, Wuhan University, Wuhan, China.
Duan
L
L
Fan
M
M
Wu
X
X
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D017209:Apoptosis / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology*; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051880:Receptors, Notch / Q000187:drug effects*; D014062:Tongue Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D014407:Tumor Cells, Cultured
D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; C000715470:MAS1 protein, human; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases