Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5.
Glioblastoma multifome is the most common and most aggressive primary brain tumor with no current curative therapy. We found expression of the bZip transcription factor ATF5 in all 29 human glioblastomas and eight human and rat glioma cell lines assessed. ATF5 is not detectably expressed by mature brain neurons and astrocytes, but is expressed by reactive astrocytes. Interference with ATF5 function or expression in all glioma cell lines tested causes marked apoptotic cell death. In contrast, such manipulations do not affect survival of ATF5-expressing cultured astrocytes or of several other cell types that express this protein. In a proof-of-principle experiment, retroviral delivery of a function-blocking mutant form of ATF5 into a rat glioma model evokes death of the infected tumor cells, but not of infected brain cells outside the tumors. The widespread expression of ATF5 in glioblastomas and the selective effect of interference with ATF5 function/expression on their survival suggest that ATF5 may be an attractive target for therapeutic intervention in such tumors.
Angelastro
J M
JM
Department of Pathology and Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY, USA. jmangelastro@ucdavis.edu
Canoll
P D
PD
Kuo
J
J
Weicker
M
M
Costa
A
A
Bruce
J N
JN
Greene
L A
LA
D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000473:pathology; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000235:genetics; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D034741:RNA, Small Interfering; D051381:Rats; D014407:Tumor Cells, Cultured
C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D034741:RNA, Small Interfering