TRAIL-induced apoptosis of FHIT-negative lung cancer cells is inhibited by FHIT re-expression.
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.
Department of Anatomy, Pharmacology & Forensic Medicine, University of Parma, Parma, Italy.
Prisco
P
Mirandola
Giuliana
G
Gobbi
Ivonne
I
Sponzilli
Chiara
C
Malinverno
Andrea
A
Cavazzoni
Roberta
R
Alfieri
Pier Giorgio
PG
Petronini
Marco
M
Vitale
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004441:Ecdysterone / Q000031:analogs & derivatives / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D004441:Ecdysterone; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; D000099170:Bis(5'-adenosyl)triphosphatase; C008999:ponasterone A