BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1-induced apoptosis in breast cancer cells.
Spongistatin 1, a marine experimental substance with chemotherapeutic potential, induces apoptosis and inhibits clonogenic survival of MCF-7 cells. Regarding the apoptotic signaling pathways of spongistatin 1, we present two major facts. Firstly, spongistatin 1-induced cell death, mainly caspase-independent, involves the proapoptotic proteins apoptosis-inducing factor and endonuclease G. Both proteins translocate from mitochondria to the nucleus and contribute to spongistatin 1-mediated apoptosis as shown via gene silencing. Secondly, spongistatin 1 acts as a tubulin depolymerizing agent and is able to free the proapoptotic Bcl-2 family member Bim from its sequestration both by the microtubular complex and by the antiapoptotic protein Mcl-1. Silencing of Bim by small interfering RNA leads to a diminished translocation of apoptosis-inducing factor and endonuclease G to the nucleus and subsequently reduces apoptosis rate. Thus, we identified Bim as an important factor upstream of mitochondria executing a central role in the caspase-independent apoptotic signaling pathway induced by spongistatin 1. Taken together, spongistatin 1 is both a valuable tool for the characterization of apoptotic pathways and a promising experimental anticancer drug.
Schneiders
Uta M
UM
Department of Pharmacy, Center for Drug Research, University of Munich, Butenandtstrasse 5-13, D-81377 Munich, Germany.
Schyschka
Lilianna
L
Rudy
Anita
A
Vollmar
Angelika M
AM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D005260:Female; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D000095702:Polyether Toxins
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D020169:Caspases; D004706:Endodeoxyribonucleases; D018942:Macrolides; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; C000606775:BCL2L11 protein, human; C083856:spongistatin 1; D000095702:Polyether Toxins; C052391:endonuclease G