Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer1-4. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
|Titolo:||Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway|
|Parole Chiave:||animal cell ; animal experiment ; animal model ; antineoplastic activity ; apoptosis ; article ; cell survival ; controlled study ; drug effect ; drug mechanism ; enzyme inhibition ; gene expression ; human cell ; human ; leukemia ; mouse ; myeloid leukemia ; nonhuman ; oncogene ; priority journal ; protein expression ; receptor sensitivity ; signal transduction ; upregulation ; FAS ligand ; Fas antigen ; death receptor ; histone eacetylase inhibitor ; histone deacetylase ; oncoprotein; promyelocytic leukemia protein ; retinoic acid ; transcription factor RUNX1 ; tumor necrosis factor related apoptosis inducing ligand ; valproic acid|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||gen-2005|
|Digital Object Identifier (DOI):||10.1038/nm1160|
|Appare nelle tipologie:||01 - Articolo su periodico|