Oocyte-based screening of cytokinesis inhibitors and identification of pectenotoxin-2 that induces Bim/Bax-mediated apoptosis in p53-deficient tumors.
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 (PTX-2), which was first identified as a cytotoxic entity in marine sponges, which depolymerizes actin filaments, 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 filaments 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 PTX-2. 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.
Chae
Hee-Don
HD
National Research Laboratory, Department of Microbiology, Dankook University College of Medicine, Anseo 29, Cheonan 330-714, Korea.
Choi
Tae-Saeng
TS
Kim
Byeong-Mo
BM
Jung
Jee H
JH
Bang
Yung-Jue
YJ
Shin
Deug Y
DY
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D048749:Cytokinesis / Q000187:drug effects; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D018942:Macrolides; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D000095702:Polyether Toxins
D000199:Actins; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D005663:Furans; D018942:Macrolides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011714:Pyrans; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; C494827:Bax protein, mouse; C000606776:Bcl2l11 protein, mouse; C098380:pectenotoxin 2; D000095702:Polyether Toxins