Role of p53 status in chemosensitivity determination of cancer cells against histone deacetylase inhibitor sodium butyrate.
Histone deacetylases inhibitors (HDIs) induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (NaB), a histone deacetylase inhibitor, has been shown to cause a G(1) cell cycle arrest by inducing p21(WAF1/CIP1) in a p53-independent manner. In this report, we present evidence for activation of p53 pathway by NaB and its role in the NaB-mediated growth suppression. Addition of NaB increased the levels of p53 involving a p14(ARF)-dependent post-transcriptional mechanism. NaB induced p53 is functional as it activated p53-specific reporter, induced the level of p21(WAF1/CIP1), inhibited cellular DNA synthesis and induced apoptosis. By using HPV 16 E6 stable transfectants as well as p53 null cancer cells, we show that NaB suppresses the growth of WT p53 containing cells more efficiently. NaB inhibited DNA synthesis to similar extent both in the presence and absence of p53. However, NaB treatment lead to a major G(2)/M arrest of cells in the presence of p53, while cells without wild-type p53 accumulated mainly in G(1) phase of the cell cycle. Furthermore, apoptosis induction by NaB is greatly reduced in the absence of p53. These results suggest that p53 pathway mediates in part growth suppression by NaB and the p53 status may be an important determinant of chemosensitivity in HDI based cancer chemotherapy.
Joseph
Jeena
J
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India.
Wajapeyee
Narendra
N
Somasundaram
Kumaravel
K
D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012323:RNA Processing, Post-Transcriptional; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012978:Sodium Oxybate / Q000494:pharmacology*; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C068651:E6 protein, Human papillomavirus type 16; D056572:Histone Deacetylase Inhibitors; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D012978:Sodium Oxybate; D004247:DNA; D001973:Bromodeoxyuridine