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.