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Cellular response and activation of apoptosis by mithramycin SK in p21(WAF1)-deficient HCT116 human colon carcinoma cells.

Abstract
HCT116 (p21(-/-)) human colon carcinoma cells treated with mithramycin SK (MSK), a novel analog of the antitumor antibiotic mithramycin A (MTA), were transiently arrested in G2/M, with some cells entering a faulty mitotic cycle without cytokinesis that resulted in G1-like cell arrest, which consisted of post-mitotic aneuploid G1 cells. Some of these cells synthesized DNA and elicited an apoptotic response. The absence of p21(WAF1) made HCT116 cells more sensitive to MSK than to the related MTA. MSK also showed higher antiproliferative activity than MTA on HCT116 cells with different genetic backgrounds, including those lacking the p53 gene. Apoptosis in MSK-treated p21(-/-) cells involved caspase 2 rather than caspase 3. Untreated HCT116 (p21(-/-)) cells presented a little caspase 3 activity, which increased slightly after treatment with MSK. The apoptotic response in p21(-/-) cells comprised caspase 2 acting as an executor caspase together with a loss of mitochondrial membrane potential that may be initiated by caspase 2. In contrast, caspase 3 was activated in wild-type HCT116 after treatment with MSK.
AuthorsMarc Bataller, Carmen Méndez, José A Salas, José Portugal
JournalCancer letters (Cancer Lett) Vol. 292 Issue 1 Pg. 80-90 (Jun 01 2010) ISSN: 1872-7980 [Electronic] Ireland
PMID19962819 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • mithramycin SK
  • Caspase 2
  • Plicamycin
Topics
  • Apoptosis (drug effects)
  • Caspase 2 (metabolism)
  • Cell Cycle (drug effects)
  • Colonic Neoplasms (genetics, pathology)
  • Cyclin-Dependent Kinase Inhibitor p21 (genetics)
  • G2 Phase
  • HCT116 Cells
  • Humans
  • Mitosis
  • Plicamycin (analogs & derivatives)
  • Tumor Cells, Cultured

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