[FLIP--an enemy which might lose the battle against the specific inhibitors of translation].
Immune- and multidrug-resistance in cancer cells resulted from complex molecular phenomena which developed and were preserved in cancer cells during evolution. Particular interest has been focused on the mechanisms that protect neoplastic cells from deletion by the cytotoxic effects induced by death ligands (TNF-alpha, CD95/APO-1/FasL, TRAIL). The intracellular protein FLIP (Casper/iFLICE/FLAME-1/CASH/CLARP/MRIT/usurpin), discovered at the end of the 1990's, is thought to be the main causal factor of "immune escape" whenever the death signal is to be initiated by the oligomerization of DISC. However, the FLIP-induced blockade of caspase-8 causing caspase-8 to remain in the inactive form and thus unable to trigger extrinsic apoptosis, does not seem to be unique to cancer cells. Numerous examples of how FLIP contributes to regulatory processes of physiological or inflammatory importance have also been described. Regardless of cell type, the final common path of Flip's negative influence on death signals results in both elevated viability and resistance to TNF-alpha and other death ligands. With regard to TNF-alpha R1, FLIP binds to FADD when DISC is formed and redirects the death signal to cell survival, with subsequent activation of NF-kappaB. In consequence, NF-kappaB can translocate to the nucleus where it transactivates several antiapoptotic genes, including flip, which leads to increased expression of FLIP protein. FLIP is distinct from other antiapoptotic or death receptor signalosome proteins by its high susceptibility to the retarded translation induced by metabolic inhibitors. In in vitro studies, such activity is exerted by cycloheximide or bisindolylmaleimide, either of which, at a low, non-toxic concentration, totally abrogates FLIP protein expression or, in turn, sensitizes cancer cells to death ligands. The assumed reduced viability/elevated mortality of cancer cells, including the most malicious (e.g. melanomas), upon treatment with specific metabolic inhibitors of FLIP makes feasible the search for synthetic or natural factors that may promise more efficacious treatment of deadly diseases where basal FLIP protein is overexpressed.
Pajak
Beata
B
Katedra Nauk Fizjologicznych, Wydział Medycyny Weterynaryjnej, Szkoła Główna Gospodarstwa Wiejskiego, Warsaw.
Orzechowski
Arkadiusz
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*; D014176:Protein Biosynthesis; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors