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.