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 cFLIPL and cFLIPs 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 cFLIPL and cFLIPS protein levels in the DNA damage response. Here, we provide genetic evidence that ATM kinase activity is required to trigger 5-FUand neocarzinostatin-dependent cFLIPL and cFLIPS downregulation, 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 cFLIPL 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. © The Author 2010. Published by Oxford University Press. All rights reserved.