Mirandola Prisco, Gobbi Giuliana, Sponzilli Ivonne, Malinverno Chiara, Cavazzoni Andrea, Alfieri Roberta, Petronini Pier Giorgio, Vitale Marco
Department of Anatomy, Pharmacology & Forensic Medicine, University of Parma, Parma, Italy.
J Cell Physiol. 2009 Aug;220(2):492-8. doi: 10.1002/jcp.21801.
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.
脆性组氨酸三联体（FHIT）是一种肿瘤抑制基因，其等位基因缺失与多种人类癌症相关。FHIT蛋白作为一种二腺苷寡磷酸水解酶，但其肿瘤抑制活性似乎与其酶活性无关。肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）可诱导FHIT阴性的非小细胞肺癌细胞系Calu-1发生凋亡。我们构建了四个可诱导FHIT表达的Calu-1细胞克隆，并证明FHIT表达能够保护细胞免受TRAIL诱导的凋亡，而不影响TRAIL受体的表面表达。对SV40永生化的正常支气管BEAS细胞进行FHIT特异性小干扰RNA转染，这些细胞中FHIT蛋白水平与正常支气管细胞相当，结果导致TRAIL诱导的凋亡显著增加。值得注意的是，苏拉明介导的对FHIT酶活性的抑制也增强了TRAIL诱导的凋亡。我们得出结论，肺癌细胞中FHIT的表达可保护细胞免受TRAIL诱导的凋亡。我们的数据表明，FHIT在TRAIL受体下游发挥这种保护作用，并且可能需要其二磷酸核苷三磷酸水解酶活性。由于TRAIL在不久的将来是基于死亡配体的抗癌治疗的良好候选者，在进行旨在恢复非小细胞肺癌肿瘤中FHIT基因表达水平的分子遗传学干预或药物诱导的表观遗传调控之前，应考虑其潜在的治疗用途。
