A significant number of malignant human tumors contain high levels of growth factor receptors. Epidermal growth factor receptor (EGF-R) overexpression or altered expression has been reported for several human tumors, particularly squamous carcinomas. We discovered that epidermal growth factor (EGF) is a radiation sensitizer of squamous carcinoma (SC) cells that overexpress the EGF-R. We hypothesize that EGF exposure prevents irradiated cells that overexpress the EGF-R from establishing an effective response to radiation-induced damage by modulating or competing for common signaling pathways. We will investigate important biochemical processes or molecular events involved in the convergence of EGF signal transduction and signals associated with radiation damage. We propose to identify components of EGF-induced radiosensitization by investigating and comparing events in two SC cell lines: A431, which is radiosensitized by EGF, and SiHa, which is not radiosensitized by EGF. A431 cells (A43l-R) will be included that allow EGF-induced radiosensitization to be separated from growth effects of EGF. Preliminary results in nonirradiated A431 and SiHa cells show significant differences in surface EGF-R density and the extent and kinetics of protein tyrosine phosphorylation. We have found in irradiated A431 cells that EGF signal transduction has points of convergence with the classical radiation-induced G2 arrest and with the effect of radiation on an EGF-induced G1 arrest. We will extend these preliminary studies and compare the extent and kinetics of tyrosine and serine/threonine phosphorylation cascades, the activities of specific mitogen-responsive kinases, and changes in the activities of specific cell-cycle control proteins in an analysis of EGF-induced radiosensitization in asynchronous and synchronous A431, A431-R, and SiHa cultures. Candidate radiosensitizing events will be those that differ significantly either quantitatively or qualitatively among the cell lines. These studies will provide insight into basic mechanisms of signaling that cause biochemical changes and changes in gene expression in response to radiation and EGF. Ultimately, this information may be used in the design of radiosensitizing strategies that exploit specific signal transduction pathways in tumor cells.
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