| Popis: |
FLIP is an anti-apoptotic protein over expressed in multiple types of cancer, including non-small cell lung cancer and associated with drug resistance and poor prognosis. Histone deacetylase inhibitors (HDACi) are identified as a class of drug which down-regulate FLIP expression in NSCLC and induce apoptosis in a FLiP-, caspase-8- and death receptor-dependent manner. Rational combinations of HDACI with the chemotherapeutic cisplatin or TRAIL are result in synergistic cell death in non-small cell lung cancer cell line models but not in normal lung fibroblast cells. More selective HDACi elicited equal or greater responses as pan-HDACi. FLIP down-regulation in response to HDACi occurs via the ubiquitin-proteasome system (UPS). Fundamental biology of FLIP's ubiquitination is examined, including identifying FLIP's ubiquitination at the death inducing signalling complex (DISC). FLIP's ubiquitination is mediated by Iysines 192 and 195 as well as phosphorylation of serene 193. The conjugation of a ubiquitin moiety to a substrate is mediated by E3 ligases, and the removal of ubiquitin is dependent on deubiquitinating enzymes. Two screens were performed to identify novel E3 ligases and DUBs which regulate FLIP's stability and ubiquitination. From these we identified potential candidates. These were validated and appear to be bona fide regulators of FLIP's ubiquitination. Better understanding of the fundamental biology of FLIP has the potential to open new avenues for therapeutic intervention for cancer treatment. |
