Modulation of apoptotic signalling by 9-hydroxystearic acid in osteosarcoma cells.
9-hydroxystearic acid (9-HSA) belongs to the class of endogenous lipid peroxidation by-products that greatly diminish in tumors, causing as a consequence the loss of one of the control mechanisms on cell division. We have previously shown that 9-HSA controls cell growth and differentiation by inhibiting histone deacetylase 1 (HDAC1) activity. In this paper our attention has not only been focused on HDAC1 inhibition but also on the hyperacetylation of other substrates such as p53, that is involved in inducing cell cycle arrest and/or apoptosis, and whose activity and stability are known to be regulated by posttranslational modifications, particularly by acetylation at the C-terminus region. 9-HSA administration to U2OS, an osteosarcoma cell line p53 wt, induces a growth arrest of the cells in G2/M and apoptosis via a mitochondrial pathway. In particular hyperacetylation of p53 induced by the HDAC1 inhibitory activity of 9-HSA has been demonstrated to increase Bax synthesis both at the transcriptional and the translational level. The subsequent translocation of Bax to the mitochondria is associated to a significant increase in caspase 9 activity. Our data demonstrate that the effects of 9-HSA on U2OS correlate with posttranslational modifications of p53.
Calonghi
N
N
Department of Biochemistry G. Moruzzi, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Pagnotta
E
E
Parolin
C
C
Molinari
C
C
Boga
C
C
Dal Piaz
F
F
Brusa
G L
GL
Santucci
M A
MA
Masotti
L
L
D000107:Acetylation; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013229:Stearic Acids / Q000494:pharmacology* / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013229:Stearic Acids; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C070375:9-hydroxystearic acid