Autophagy and the functional roles of Atg5 and beclin-1 in the anti-tumor effects of 3beta androstene 17alpha diol neuro-steroid on malignant glioma cells.

Abstract

In this study, we demonstrate that the anti-tumor activity of the neuro-steroid, 3beta androstene 17alpha diol (17alpha-AED) on malignant glioma cells is mediated by the induction of autophagy. 17alpha-AED can inhibit the proliferation an induce cell death of multiple, unrelated gliomas with an IC(50) between 8 and 25muM. 17alpha-AED treatment induced the formation of autophagosomes and acidic vesicular organelles in human malignant gliomas which was blocked by bafilomycin A1 or 3-methyladenine. Cleavage of microtubule-associated protein-light chain 3 (LC3), an essential step in autophagosome formation, was detected in human malignant glioma cells exposed to 17alpha-AED. In 17alpha-AED treated T98G glioma cells there was an increase in the autophagy related proteins Atg5 and beclin-1. Silencing of ATG5 or beclin-1 with small interfering RNA significantly reduced the incidence of autophagy in 17alpha-AED treated malignant gliomas and attenuated the cytotoxic effects of the neuro-steroid indicating that the induction of autophagy mediates the anti-glioma activity of 17alpha-AED rather than serving as a cyto-protective response. These results demonstrate that 17alpha-AED possesses significant anti-glioma activity when used at pharmacologically relevant concentrations in vitro and the cytotoxic effects are resultant from the induction of autophagy.

• Authors: Martin R Graf, Wentao Jia, Ross S Johnson, Paul Dent, Clint Mitchell, Roger M Loria
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 115 Issue 3-5 Pg. 137-45 (Jul 2009) ISSN: 1879-1220 [Electronic] England
• PMID: 19375507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATG5 protein, human
• Anabolic Agents
• Apoptosis Regulatory Proteins
• Autophagy-Related Protein 5
• BECN1 protein, human
• Beclin-1
• Membrane Proteins
• Microtubule-Associated Proteins
• RNA, Small Interfering
• Androstane-3,17-diol
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Anabolic Agents (chemistry, pharmacology)
• Androstane-3,17-diol (chemistry, pharmacology)
• Animals
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects)
• Autophagy-Related Protein 5
• Beclin-1
• Cell Line, Tumor (drug effects)
• Glioma (metabolism, pathology)
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Microtubule-Associated Proteins (genetics, metabolism)
• Organelles (metabolism)
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Rats
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases