TY - JOUR
T1 - Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway
AU - Insinga, Alessandra
AU - Monestiroli, Silvia
AU - Ronzoni, Simona
AU - Gelmetti, Vania
AU - Marchesi, Francesco
AU - Viale, Andrea
AU - Altucci, Lucia
AU - Nervi, Clara
AU - Minucci, Saverio
AU - Pelicci, Pier Giuseppe
N1 - Funding Information:
We thank E. Grassilli, M. Faretta, F. Padula, R. Fiorini and D. Croci for discussions. This work was supported by grants from European Community (QLG1-CT-2001-01935), Ministero dell’ Istruzione, dell’Universita’ e della Ricerca and Associazione Italiana per la Ricerca sul Cancro to P.G.P. and S.M., and from Fondazione Monzino to P.G.P.
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nm1160
DO - 10.1038/nm1160
M3 - Article
C2 - 15619634
AN - SCOPUS:13444274622
SN - 1078-8956
VL - 11
SP - 71
EP - 76
JO - Nature medicine
JF - Nature medicine
IS - 1
ER -