Erb-B receptor-mediated survival mechanisms to ionizing radiation in carcinoma cells

The Erb-B family of RTKs couple specific autocrine growth factor activation of a receptor to signal transduction cassettes that are recruited by receptor phosphorylation. Dimerization of Erb-B receptor family members diversifies these cellular signals based upon the endogenous RTK complement. For carcinoma cells, which usually express multiple Erb-B RTK types, both complementary and redundant signals are initiated by this mechanism. Because radiation is an indiscriminate activator of these RTKs, it has the potential to stimulate both mitogenic and anti-apoptotic signaling pathways to evade radiation induced cell death. Our hypothesis is that the identification and manipulation of these pathways may provide insight to enhancing IR toxicity in carcinomas.; In investigations of A431 and MDA cell lines, we identified Erb-B dependent signaling to both Akt and p70 S6K. A direct relationship between Erb-B2 and Akt stimulation was observed, and this activity was also correlated with apoptotic responses following IR. The IR-induced activation of p70S6K is another protective pathway that was shown to have multiple Erb-B receptor components that generate parallel signals to modulate ribosomal translation. Together these results demonstrate the importance of blocking multiple Erb-B receptors to radiosensitize carcinoma cells.; The EGFR-CD533 produces trans-inhibition of RTKs and combines with radiation in multiple carcinoma cell types to reduce clonogenic survival. We therefore investigated the effects of EGFR-CD533 and Erb-B2-CD572, a similar but distinct Erb-B deletion mutant, on growth factor and IR stimulation of Erb-B RTKs as well as the effects on down stream signal transduction. These results identified the broad spectrum of Erb-B RTK inhibition produced by the EGFR-CD533 and illustrated that partial inhibition of the Erb-B RTK network was not sufficient to produce radio sensitization.; Our investigations were geared to identify mechanisms that could (1) produce radiosensitization when blocked or (2) could compensate for Erb-B inhibition and contribute to radioresistance. In T47D cells, we identified a novel, protective signaling pathway between Erb-B3 and Src. Src is sensitive to EGFR or Erb-B2 inhibition, however endogenous or ectopically expressed Erb-B3 maintained Src autophosphorylation during trans-receptor inhibition with the EGFR-CD533. This c-Src activity was correlated with a survival signal, that when blocked, enhanced radiation induced apoptosis. These studies suggest that Erb-B3 expression should be considered in potential therapeutic strategies that target EGFR and Erb-B2.