title: ATM kinase activity modulates cFLIP protein levels: potential interplay between DNA damage signalling and TRAIL-induced apoptosis.
abstract: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed as a potent tool to trigger apoptosis in cancer therapy. However, since ∼60% of tumour cell lines and most primary cancers are resistant to TRAIL-induced apoptosis, several combined therapy approaches aimed to sensitize cells to TRAIL have been developed. One of the major targets of these approaches are cFLIP proteins as they interfere with the initiation of apoptosis induction by TRAIL, are over-expressed in many cancers and their down-regulation enhances TRAIL sensitivity. Although, DNA-damaging agents such as 5-fluorouracil (5-FU), etoposide and adriamycin have been successfully employed due to their ability to trigger cFLIP(L) and cFLIP(s) down-regulation the molecular mechanisms underneath their action have been only partially elucidated. We have recently identified ataxia telangiectasia mutated (ATM) as a modulator of cFLIP(L) and cFLIP(S) protein levels in the DNA damage response. Here, we provide genetic evidence that ATM kinase activity is required to trigger 5-FU- and neocarzinostatin-dependent cFLIP(L) and cFLIP(S) down-regulation, which in turn sensitize hepatocellular carcinoma (HCC) cell lines to TRAIL. ATM activity triggers cFLIP proteins down-regulation in HCC cells independently on p53 and enhances cFLIP(L) ubiquitination in response to DNA damage. Therefore, we propose that ATM kinase mediates the interplay between DNA damage and death receptor signalling and suggest that expression of catalytically competent ATM in tumour cells may play a key role for successful combinatorial use of TRAIL receptor agonists and DNA-damaging drugs in cancer therapy.
authors.affiliation: Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.
authors.forename: Venturina
authors.initials: V
authors.lastname: Stagni
authors.forename: Michele
authors.initials: M
authors.lastname: Mingardi
authors.forename: Simonetta
authors.initials: S
authors.lastname: Santini
authors.forename: Danilo
authors.initials: D
authors.lastname: Giaccari
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D009353:Zinostatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil