Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells

Donald M. O'Rourke, Gary D. Kao, Natasha Singh, Byeong Woo Park, Ruth J. Muschel, Chuan Jin Wu, Mark I. Greene

Research output: Contribution to journalArticle

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Abstract

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 γ-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 γ-irradiation and other cytotoxic therapies, and this approach suggests that present anticancer strategies could be optimized.

Original languageEnglish
Pages (from-to)10842-10847
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number18
DOIs
Publication statusPublished - 1998 Sep 1

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Apoptosis
Phenotype
DNA Damage
Neoplasms
Growth
Neuroglia
Radiation
Oncogene Proteins
p53 Genes
Glioblastoma
Cell Cycle Checkpoints
Serum
Glioma
Cell Death
ErbB Receptors
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

O'Rourke, Donald M. ; Kao, Gary D. ; Singh, Natasha ; Park, Byeong Woo ; Muschel, Ruth J. ; Wu, Chuan Jin ; Greene, Mark I. / Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells. In: Proceedings of the National Academy of Sciences of the United States of America. 1998 ; Vol. 95, No. 18. pp. 10842-10847.
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Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells. / O'Rourke, Donald M.; Kao, Gary D.; Singh, Natasha; Park, Byeong Woo; Muschel, Ruth J.; Wu, Chuan Jin; Greene, Mark I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 18, 01.09.1998, p. 10842-10847.

Research output: Contribution to journalArticle

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