Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway

Abstract

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.

Histone deacetylase inhibitors: molecular mechanisms of action

“…HDACi-induced cell death can be reduced by chimeras of DR5-Fc (anti-TRAIL) or Fas-Fc (antiFas), monoclonal antibodies against FasL or TRAIL and small inhibitor RNA (siRNA) of TRAIL or Fas (Nakata et al, 2004;Insinga et al, 2005;Rosato and Grant, 2005). Taken together, the data indicate that the extrinsic apoptotic pathway can account for HDACiinduced cell death in many transformed cells.…”

“…Normal cells are relatively resistant to HDACi-induced cell death (Burgess et al, 2004;Insinga et al, 2005;Ungerstedt et al, 2005). The cell death pathways identified in mediating HDACiinduced transformed cell death include apoptosis (Rosato and Grant, 2005;Bolden et al, 2006;Minucci and Pelicci, 2006) by the intrinsic (Ruefli et al, 2001) and extrinsic pathways, mitotic catastrophe/cell death (Qiu et al, 2000;Dowling et al, 2005;Xu et al, 2005), autophagic cell death (Shao et al, 2004), senescence and reactive oxygen species (ROS)-facilitated cell death (Rosato and Grant, 2005;Ungerstedt et al, 2005).…”

“…HDACi can upregulate the expression of both death receptors and their ligands, in vitro and in vivo, in transformed cells, but not in normal cells (Nakata et al, 2004;Insinga et al, 2005). Fas and FasL were induced in human neuroblastoma cells by M-carboxycinnamic acid bihydroxamide (Glick et al, 1999), nude mice xenograft of human osteosarcoma cells by FK228, and mouse model of APL by VPA (Insinga et al, 2005).…”

“…HDACi can upregulate the expression of both death receptors and their ligands, in vitro and in vivo, in transformed cells, but not in normal cells (Nakata et al, 2004;Insinga et al, 2005). Fas and FasL were induced in human neuroblastoma cells by M-carboxycinnamic acid bihydroxamide (Glick et al, 1999), nude mice xenograft of human osteosarcoma cells by FK228, and mouse model of APL by VPA (Insinga et al, 2005). TRAIL and its receptor DR-5 were induced in the mouse model of APL by VPA (Insinga et al, 2005), and Jurkat human T-cell lymphoblast leukemia cells and SKW6.4B lymphoblast cells by LAQ824 (Rosato et al, 2006).…”

“…Fas and FasL were induced in human neuroblastoma cells by M-carboxycinnamic acid bihydroxamide (Glick et al, 1999), nude mice xenograft of human osteosarcoma cells by FK228, and mouse model of APL by VPA (Insinga et al, 2005). TRAIL and its receptor DR-5 were induced in the mouse model of APL by VPA (Insinga et al, 2005), and Jurkat human T-cell lymphoblast leukemia cells and SKW6.4B lymphoblast cells by LAQ824 (Rosato et al, 2006). HDACi upregulated DR-5 in various transformed cells.…”