title: Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells.
abstract: In this study we have investigated the effects of low dose ionizing radiation (2 Gy) on p70 S6 kinase and Akt signaling with respect to Erb-B receptors in both the A431 squamous and the MDA-MB-231 mammary carcinoma cell lines. Ionizing radiation caused a 2-3-fold increase in p70 S6 kinase activity that was blocked pharmacologically using an EGFR inhibitor (AG1478) alone, or in combination with an Erb-B2 inhibitor (AG825). These results suggested that both EGFR and Erb-B2 receptors could initiate radiation-induced activation of p70 S6K. EGFR dependent Erb-B3 signaling also contributed to p70 S6 kinase activity through recruitment and activation of PI3K, which has been shown to regulate p70 S6 kinase activity. Furthermore, inhibition of the EGFR blocked IR stimulated increases in protein translation, a biologic consequence of p70 S6 kinase activation. We also report that ionizing radiation stimulated Akt activity that was partially independent of PI3K activity, but dependent on Erb-B2 function. Erb-B2 inhibition also correlated with enhanced apoptosis following IR exposure, suggesting an important role for Erb-B2 in cell survival. Together this work demonstrates that the Erb-B receptor tyrosine kinase network stimulates cytoprotective p70 S6 kinase and Akt activity in response to clinically relevant doses of ionizing radiation.
authors.affiliation: The Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Contessa
authors.forename: Jaime
authors.initials: J
authors.lastname: Hampton
authors.forename: Guido
authors.initials: G
authors.lastname: Lammering
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mikkelsen
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.forename: Rupert K
authors.initials: RK
authors.lastname: Schmidt-Ullrich
mesh_terms: D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D020935:MAP Kinase Signaling System / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D011839:Radiation, Ionizing; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D066246:ErbB Receptors; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D019893:Ribosomal Protein S6 Kinases; C494918:AKT1 protein, human