Mithramycin SK modulates polyploidy and cell death in colon carcinoma cells.
During a normal cell cycle, polyploidy and aneuploidy can be prevented by several checkpoints, which are mainly p53 dependent. Here, we show that treatment of HCT-116 (p53+/+) colon carcinoma cells with the novel antitumor antibiotic mithramycin SK (MSK) results in polyploidization and mitotic catastrophe, which occurs after a transient halt in G1 phase followed by the overtaking of the G2-M checkpoint when treated cells are incubated in a fresh drug-free medium. Cells reentering aberrant mitosis mainly died by necrosis, although active caspase-3 was observed. Our results indicate that a decrease in p53 RNA and protein levels, together with concomitant changes in the expression of other proteins such as p21WAF1, were involved in MSK-induced polyploidy. Furthermore, the effects of MSK on HCT-116 (p53+/+) cells cannot be attributed exclusively to the down-regulation of p53 by MSK, because these effects differed from those observed in MSK-treated HCT-116 (p53-/-) cells. The p53(-/-) cells died mainly from G2-M through early p53-independent apoptosis, which appeared to be mediated by caspase-2, although secondary necrosis was also observed.
Bataller
Marc
M
Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, Baldiri Reixach, 10, E-08028 Barcelona, Spain.
Méndez
Carmen
C
Salas
José A
JA
Portugal
José
J
D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D048749:Cytokinesis / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009336:Necrosis; D009363:Neoplasm Proteins / Q000378:metabolism; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011123:Polyploidy; D014158:Transcription, Genetic / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; C520007:mithramycin SK; C066851:mithramycin A; D008926:Plicamycin