Transcriptional changes facilitate mitotic catastrophe in tumour cells that contain functional p53.
Exposure of Jurkat T lymphocytes containing functional p53 to nanomolar concentrations of bisanthracycline WP631 resulted in arrest at the G2/M checkpoint and transient senescence-like phenotype in the presence of DNA synthesis. The cells entered crisis, became polyploid, showed aberrant mitotic figures, and died through mitotic catastrophe. Cell death was accompanied by changes in the expression profile of various oncogenes and tumour suppressor genes including the down-regulation of p53. The changed expression was confirmed for some of these genes using semi-quantitative RT-PCR, and the decline in p53 protein levels was established. Our results suggest that WP631 induced changes in cell cycle control pathways leading to death of Jurkat T cells through mitotic catastrophe, which occurred in the absence of caspase-2 and caspase-3 activities, rather than apoptosis.
Mansilla
Sylvia
S
Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Josep Samitier, 1-5, E-08028 Barcelona, Spain.
Priebe
Waldemar
W
Portugal
José
J
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D019169:Jurkat Cells; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011123:Polyploidy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C104426:WP 631; D019098:Telomerase; D053143:Caspase 2; D053148:Caspase 3; D003630:Daunorubicin