HDAC inhibitors induce apoptosis but not cellular senescence in Gadd45α-deficient E1A+Ras cells.
HDAC inhibitors (HDIs) induce irreversible cell cycle arrest and senescence in E1A+Ras expressing cells. Furthermore, HDIs activate Gadd45α/NF-κB signaling pathway to suppress apoptosis thereby promoting the cell survival. Here, to clarify the role of Gadd45α in realization of the antiapoptotic program, we compared wild-type E1A+Ras cells and the cells with knockout of gadd45α gene (Gadd45α-/- cells). As in Gadd45α-expressing E1A+Ras cells, HDIs induce irreversible cell cycle arrest in Gadd45α-/- cells, but the arrested cells do not senesce and eventually die due to activation of the apoptotic death program. These data suggest that the expression of Gadd45α is involved in maintaining the balance of pro- and anti-apoptotic stimuli, while lack or loss of Gadd45 directs the cells to apoptosis after HDIs treatment. Appropriately Gadd45α-deficient cells demonstrate a higher level of pro-apoptotic signals, whereas the anti-apoptotic program is suppressed. The elevated apoptotic background of Gadd45α-/- cells is accompanied by higher levels of Ser15-phosphorylated p53 and p21/Waf1 proteins that additionally commit the cells to HDIs-induced apoptosis. Additionally, loss of Gadd45α protein activates the DDR signaling pathway as demonstrated by nuclear pATM staining, accumulation of γH2AX foci and an increase of single-strand DNA breaks. Thus, in wild-type E1A+Ras cells the p53-dependent expression of Gadd45α is necessary not only for DNA repair and HDI-induced cellular senescence, but also to withstand to apoptosis after DNA damage and stress. Therefore the use of HDIs in combination with agents that block Gadd45α function may have promise for cancer therapy.
Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia; St. Petersburg State University, Russia. Electronic address: marie.igotti@gmail.com.
M V
MV
Igotti Abramova
University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA(1).
A K
AK
Pojidaeva
St. Petersburg State University, Russia.
E A
EA
Filippova
St. Petersburg State University, Russia.
O O
OO
Gnedina
Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia; St. Petersburg State University, Russia.
S B
SB
Svetlikova
Institute of Cytology, Russian Academy of Sciences, St-Petersburg, Russia; St. Petersburg State University, Russia.
V A
VA
Pospelov
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D055786:Gene Knockout Techniques; D011905:Genes, ras; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism; D000097642:GADD45 Proteins
D017500:Adenovirus E1A Proteins; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D009687:Nuclear Proteins; D018631:ras Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
Apoptosis; Gadd45α inactivation; HDAC inhibitors; Senescence; Transformed cells