TRAIL is a key target in S-phase slowing-dependent apoptosis induced by interferon-beta in cervical carcinoma cells.
Interferon (IFN)-beta induces S-phase slowing and apoptosis in human papilloma virus (HPV)-positive cervical carcinoma cell line ME-180. Here, we show that apoptosis is a consequence of the S-phase lengthening imposed by IFN-beta, demonstrating the functional correlation between S-phase alteration and apoptosis induction. In ME-180 cells, where p53 function is inhibited by HPV E6 oncoprotein, IFN-beta effects on cell cycle and apoptosis occur independently of p53. The apoptosis due to IFN-beta is mediated by the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a manner dependent on the S-phase deregulation. IFN-beta appears to increase TRAIL expression both directly at the mRNA level and indirectly by augmenting surface protein levels as a consequence of the induced S-phase cell accumulation. Moreover, the alteration of the S-phase due to IFN-beta promotes TRAIL-dependent apoptosis by potentiating cell sensitivity to TRAIL, possibly through induction of a proapoptotic NF-kappaB activity and TRAIL-R2 receptor expression. Interestingly, IFN-beta-induced TRAIL-dependent apoptotic events strongly differ in the requirement of caspase activity. These results show that IFN-beta may induce an apoptotic response by deregulating cell cycle. Understanding the linkage between these mechanisms appears to be of primary importance in the search for new IFN-based therapeutic strategies to circumvent cancer disease or improve clinical outcome.
Vannucchi
Serena
S
Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
Chiantore
Maria V
MV
Fiorucci
Gianna
G
Percario
Zulema A
ZA
Leone
Stefano
S
Affabris
Elisabetta
E
Romeo
Giovanna
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002277:Carcinoma / Q000473:pathology* / Q000821:virology; D020169:Caspases / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D027383:Papillomaviridae / Q000472:pathogenicity; D012333:RNA, Messenger / Q000032:analysis; D016196:S Phase; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology* / Q000821:virology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D020169:Caspases