Reversal of p53 epigenetic silencing in multiple myeloma permits apoptosis by a p53 activator.
Inactivation of the p53 pathway is a common feature of neoplasia. Dysregulation of the p53 pathway has been shown to involve mutations of p53, increased expression of the p53 inhibitor HDM-2, or epigenetic silencing of the p53 promoter. In multiple myeloma, a neoplasia of terminally differentiated B cells, p53 mutations and deletions are relatively rare and occur in late stage disease. Here, we show that the p53 promoter is hypermethylated in several multiple myeloma cell lines in comparison to normal plasma cells. Two cell lines containing mutant p53, Lp-1 and OPM-2, show a methylation pattern that suggests that they contain one methylated and one unmethylated mutant allele. Two other cell lines, KMS-11 and OPM-2, show hypermethylation of p53 with a lack of expression. In all cell lines tested, treatment with a demethylating agents results in higher expression of p53. Furthermore, following increased expression of p53, treatment of the myeloma cell lines with a p53 activating peptide induces apoptosis. Therefore, combinatorial treatment with demethylating agents followed by delivery of a p53 activating peptide may be an effective therapeutic strategy against multiple myeloma.
Hurt
Elaine M
EM
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Thomas
Suneetha B
SB
Peng
Benjamin
B
Farrar
William L
WL
D000595:Amino Acid Sequence; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D003562:Cytidine / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D016158:Genes, p53 / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D010455:Peptides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C487567:retro-inverso-TATp53C' peptide; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside