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Oocyte-based screening of cytokinesis inhibitors and identication of pectenotoxin-2 that induces Bim/Bax-mediated apoptosis in p53-deficient tumors

Cited 50 time in Web of Science Cited 54 time in Scopus
Authors
Chae, Hee-Don; Choi, Tae-Sang; Kim, Byeong-Mo; Jung, Jee H.; Bang, Yung-Jue; Shin, Deug Y.
Issue Date
2005-07
Citation
Oncogene, Vol.24 No.30, pp.4813-4819
Keywords
p53apoptosisactin inhibitorchemosensitivityBimBax
Abstract
In this study, we demonstrate that a loss of p53 sensitizes tumor cells to actin damage. Using a novel oocyte-based screening system, we identified natural compounds that inhibit cytokinesis. Among these, pectenotoxin-2 (PTX2), which was first identified as a cytotoxic entity in marine sponges, which depolymerizes actin. laments, was found to be highly effective and more potent to activate an intrinsic pathway of apoptosis in p53-deficient tumor cells compared to those with functional p53 both in vitro and in vivo. Other agents that depolymerize or knot actin. laments were also found to be toxic to p53-deficient tumors. In p53-deficient cells, PTX-2 triggers apoptosis through mitochondrial dysfunction, and this is followed by the release of proapoptotic factors and caspase activation. Furthermore, we observed Bax activation and Bim induction only in p53-deficient cells after PTX-2 treatment. RNA interference of either Bim or Bax resulted in the inhibition of caspases and apoptosis induced by PTX2. However, the small interfering RNAs (SiRNA) of Bim blocked a conformational change of Bax, but Bax SiRNA did not affect Bim expression. Therefore, these results suggest that Bim triggers apoptosis by activating Bax in p53-deficient tumors upon actin damage, and that actin inhibitors may be potent chemotherapeutic agents against p53-deficient tumors.
ISSN
0950-9232
URI
https://hdl.handle.net/10371/173207
DOI
https://doi.org/10.1038/sj.onc.1208640
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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