title: HDAC inhibitor-induced activation of NF-κB prevents apoptotic response of E1A+Ras-transformed cells to proapoptotic stimuli.
abstract: HDAC inhibitors (HDACIs) are capable of suppressing the cell growth of tumour cells due to the induction of apoptosis and/or cell cycle arrest. This allows of considering HDACIs as promising agents for tumour therapy. The final outcome - apoptotic cell death or cell cycle arrest - depends on the type of tumour and cellular context. In this report, we addressed the issue by analysing effects produced in E1A+Ras-transformed MEF cells by HDAC inhibitors sodium butyrate (NaB), Trichostatin A (TSA) and some others. It has been shown that the HDACIs induced cell cycle arrest in E1A+Ras-transformed cells but not apoptosis. The antiapoptotic effect of HDACIs is likely to be a result of NF-κB-dependent signaling pathway activation. HDACI-induced activation of NF-κB takes place in spite of a deregulated PI3K/Akt pathway in E1A+Ras cells, suggesting an alternative mechanism for the activation of NF-κB based on acetylation. HDACI-dependent activation of NF-κB prevents the induction of apoptosis by cytostatic agent adriamycin and serum deprivation. Accordingly, suppression of NF-κB activity in HDACI-arrested cells by the chemical inhibitor CAPE or RelA-siRNA resulted in the induction of an apoptotic programme. Thus, our findings suggest that the activation of the NF-κB pathway in HDACI-treated E1A+Ras-transformed cells blocks apoptosis and may thereby play a role in triggering the programme of cell cycle arrest and cellular senescence.
authors.affiliation: Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia. mav_2004@mail.ru
authors.forename: M V
authors.initials: MV
authors.lastname: Abramova
authors.forename: E A
authors.initials: EA
authors.lastname: Zatulovskiy
authors.forename: S B
authors.initials: SB
authors.lastname: Svetlikova
authors.forename: V A
authors.initials: VA
authors.lastname: Pospelov
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts; D005434:Flow Cytometry; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: D017500:Adenovirus E1A Proteins; D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D004317:Doxorubicin; D015689:Oncogene Protein p21(ras)