Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway.
Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. 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.
Insinga
Alessandra
A
Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Monestiroli
Silvia
S
Ronzoni
Simona
S
Gelmetti
Vania
V
Marchesi
Francesco
F
Viale
Andrea
A
Altucci
Lucia
L
Nervi
Clara
C
Minucci
Saverio
S
Pelicci
Pier Giuseppe
PG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D056572:Histone Deacetylase Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53