BH3-only proteins Mcl-1 and Bim as well as endonuclease G are targeted in spongistatin 1–induced apoptosis in breast cancer cells

• Published in: Molecular cancer therapeutics 2009-10, Vol.8 (10), p.2914-2925
• Main Authors: Schneiders, Uta M, Schyschka, Lilianna, Rudy, Anita, Vollmar, Angelika M
• Format: Article
• Language: English
• Subjects: AIF; Animals; Apoptosis - drug effects; Apoptosis Inducing Factor - metabolism; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Bim; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Caspases - metabolism; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Cell Survival - drug effects; chemoresistance; Endodeoxyribonucleases - metabolism; EndoG; Female; Humans; Macrolides - pharmacology; Membrane Proteins - metabolism; microtubules; Mitochondria - drug effects; Mitochondria - metabolism; Myeloid Cell Leukemia Sequence 1 Protein; Protein Binding - drug effects; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; spongistatin 1; Time Factors; Transfection; Tubulin - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-1179

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. [Mol Cancer Ther 2009;8(10):2914–25]