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Mithramycin SK modulates polyploidy and cell death in colon carcinoma cells

AuthorsBataller, Marc ; Méndez, Carmen; Salas, José A.; Portugal, José
Issue Date2008
PublisherAmerican Association for Cancer Research
CitationMolecular Cancer Therapeutics 7(9): 2988-2997 (2008)
AbstractDuring 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 p21 WAF1, 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. Copyright © 2008 American Association for Cancer Research.
Publisher version (URL)http://dx.doi.org/10.1158/1535-7163.MCT-08-0420
Identifiersdoi: 10.1158/1535-7163.MCT-08-0420
issn: 1535-7163
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