Fragile histidine triad (FHIT) is a tumor suppressor gene whose allelic loss is associated to a number of human cancers. FHIT protein acts as a diadenosine oligophosphate hydrolase, but its tumor suppressive activity appears as independent from its enzymatic activity. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) can induce apoptosis in the FHIT-negative non-small lung cancer cell line Calu-1. We generated four FHIT-inducible Calu-1 cell clones and demonstrated that FHIT expression was able to protect cells from TRAIL-induced apoptosis, without affecting TRAIL-receptors surface expression. FHIT-specific small interference RNA transfection of SV40-immortalized normal bronchial BEAS cells that show levels of FHIT protein comparable to those of normal bronchial cells, resulted in a significant increase of TRAIL-induced apoptosis. Of note, suramin-mediated inhibition of FHIT enzymatic activity also enhanced TRAIL-induced apoptosis. We conclude that FHIT expression in lung cancer cells is protective from TRAIL-induced apoptosis. Our data suggest that FHIT exerts this protective effect downstream TRAIL-receptors and likely requires its dinucleoside-triphosphate hydrolase activity. As TRAIL represents in the near future a good candidate for death ligands-based anticancer therapy, its potential therapeutic use should be envisaged as preliminary to molecular genetics interventions or drug-induced epigenetic modulations aimed to restoring FHIT gene expression levels in non-small cells lung tumors.
TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression / P. Mirandola, G. Gobbi, I. Sponzilli, C. Malinverno, A. Cavazzoni, R. Alfieri, P.G. Petronini, M. Vitale. - In: JOURNAL OF CELLULAR PHYSIOLOGY. - ISSN 0021-9541. - 220:2(2009 Aug), pp. 492-498.
|Titolo:||TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression|
|Parole Chiave:||Acid Anhydride Hydrolases; Apoptosis; Cell Line, Tumor; Ecdysterone; Epithelial Cells; Humans; Lung Neoplasms; Neoplasm Proteins; RNA, Small Interfering; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; X-Linked Inhibitor of Apoptosis Protein; Medicine (all); Physiology; Clinical Biochemistry; Cell Biology|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||ago-2009|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/jcp.21801|
|Appare nelle tipologie:||01 - Articolo su periodico|