Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway
Open Access
- 9 May 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Neuro-Oncology
- Vol. 13 (6), 622-634
- https://doi.org/10.1093/neuonc/nor023
Abstract
Glioblastoma multiforme (GBM) is a devastating disease, and the current therapies have only palliative effect. Evidence is mounting to indicate that brain tumor stem cells (BTSCs) are a minority of tumor cells that are responsible for cancer initiation, propagation, and maintenance. Therapies that fail to eradicate BTSCs may ultimately lead to regrowth of residual BTSCs. However, BTSCs are relatively resistant to the current treatments. Development of novel therapeutic strategies that effectively eradicate BTSC are, therefore, essential. In a previous study, we used patient-derived GBM sphere cells (stemlike GBM cells) to enrich for BTSC and identified maternal embryonic leucine-zipper kinase (MELK) as a key regulator of survival of stemlike GBM cells in vitro. Here, we demonstrate that a thiazole antibiotic, siomycin A, potently reduced MELK expression and inhibited tumor growth in vivo. Treatment of stemlike GBM cells with siomycin A resulted in arrested self-renewal, decreased invasion, and induced apoptosis but had little effect on growth of the nonstem cells of matched tumors or normal neural stem/progenitor cells. MELK overexpression partially rescued the phenotype of siomycin A–treated stemlike GBM cells. In vivo, siomycin A pretreatment abraded the sizes of stemlike GBM cell–derived tumors in immunodeficient mice. Treatment with siomycin A of mice harboring intracranial tumors significantly prolonged their survival period compared with the control mice. Together, this study may be the first model to partially target stemlike GBM cells through a MELK-mediated pathway with siomycin A to pave the way for effective treatment of GBM.This publication has 45 references indexed in Scilit:
- Metabolic and molecular imaging in neuro-oncologyThe Lancet Neurology, 2007
- The AMP-activated protein kinase pathway – new players upstream and downstreamJournal of Cell Science, 2004
- Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human GlioblastomaCancer Research, 2004
- Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressorGenes & Development, 2004
- ARK5 Is a Tumor Invasion-Associated Factor Downstream of Akt SignalingMolecular and Cellular Biology, 2004
- Transcription factors in liver development, differentiation, and regenerationJournal of Hepatology, 2003
- Cancerous stem cells can arise from pediatric brain tumorsProceedings of the National Academy of Sciences of the United States of America, 2003
- Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferationNature, 2003
- Stem cells, cancer, and cancer stem cellsNature, 2001
- New member of the Snf1/AMPK kinase family,Melk, is expressed in the mouse egg and preimplantation embryoMolecular Reproduction and Development, 1997