Histone deacetylase inhibitors increase p21(WAF1) and induce apoptosis of human myeloma cell lines independent of decreased IL-6 receptor expression.
Histone deacetylase (HDAC) inhibitors cause growth arrest and apoptosis of cancer cells by both p21-dependent and independent mechanisms. Decreased expression of growth factor receptors may be a key factor in the p21-independent mechanism, although this has not been directly tested. We have tested the effects of sodium butyrate and trichostatin A on human myeloma cell lines and have observed G1 arrest and apoptosis associated with increased expression of p21(WAF1), Bax, Rb dephosphorylation, and decreased IL-6 receptor (IL-6R) expression. Experiments to determine the role of disruption of IL-6 signaling as a result of decreased IL-6 receptor expression in mediating these effects were conducted using a stable transfectant of the OPM-2 line which constitutively expressed the IL-6 receptor. Our results indicated that decreased IL-6R expression was not required for induction of p21(WAF1) or apoptosis. Thus, HDAC inhibitors appear to activate multiple cellular pathways, leading to growth arrest and apoptosis, and their use in the treatment of myeloma, particularly in combination with other agents, warrants further investigation.
Lavelle
D
D
VA Chicago, Westside Division, Chicago, Illinois 60612, USA. dlavelle@uic.edu
Chen
Y H
YH
Hankewych
M
M
DeSimone
J
J
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019947:Receptors, Interleukin-6; D051028:bcl-2-Associated X Protein; C012589:trichostatin A