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 transf ormed glial cells by disabling erbB receptor signaling. However, recen t evidence indicates that the induction of apoptosis may underlie succ essful therapy of human cancers. In these studies, we examined whether disabling oncoproteins of the erbB receptor family would sensitize tr ansformed human glial cells to the induction of genomic damage by gamm a-irradiation. Radioresistant human glioblastoma cells in which erbB r eceptor signaling was inhibited exhibited increased growth arrest and apoptosis in response to DNA damage. Apoptosis was observed after radi ation in human glioma cells containing either a wild-type or mutated p 53 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 al so capable of growth arrest in serum-deprived conditions and in respon se to DNA damage, apoptotic cell death was not induced simply as a res ult of impaired growth arrest pathways. Notably, inhibition of erbB si gnaling was a more potent stimulus for the induction of apoptosis than prolonged serum deprivation. Proximal receptor interactions between e rbB receptor members thus influence cell cycle checkpoint pathways act ivated 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 opt imized.