Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells.
Inhibition of cell growth and transformation can be achieved in transformed glial cells by disabling erbB receptor signaling. However, recent evidence indicates that the induction of apoptosis may underlie successful therapy of human cancers. In these studies, we examined whether disabling oncoproteins of the erbB receptor family would sensitize transformed human glial cells to the induction of genomic damage by gamma-irradiation. Radioresistant human glioblastoma cells in which erbB receptor signaling was inhibited exhibited increased growth arrest and apoptosis in response to DNA damage. Apoptosis was observed after radiation in human glioma cells containing either a wild-type or mutated p53 gene product and suggested that both p53-dependent and -independent mechanisms may be responsible for the more radiosensitive phenotype. Because cells exhibiting increased radiation-induced apoptosis were also capable of growth arrest in serum-deprived conditions and in response to DNA damage, apoptotic cell death was not induced simply as a result of impaired growth arrest pathways. Notably, inhibition of erbB signaling was a more potent stimulus for the induction of apoptosis than prolonged serum deprivation. Proximal receptor interactions between erbB receptor members thus influence cell cycle checkpoint pathways activated in response to DNA damage. Disabling erbB receptors may improve the response to gamma-irradiation and other cytotoxic therapies, and this approach suggests that present anticancer strategies could be optimized.
O'Rourke
D M
DM
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. orourked@mail.med.upenn.edu
Kao
G D
GD
Singh
N
N
Park
B W
BW
Muschel
R J
RJ
Wu
C J
CJ
Greene
M I
MI
D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005720:Gamma Rays; D016158:Genes, p53; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors