Exposure of
tumor cells to ionizing radiation causes compensatory activation of multiple intracellular survival signaling pathways to maintain viability. In human
carcinoma cells, radiation exposure caused an initial rapid inhibition of
protein tyrosine phosphatase function and the activation of
ERBB receptors and downstream signaling pathways. Radiation-induced activation of extracellular regulated
kinase (ERK)1/2 promoted the cleavage and release of paracrine
ligands in
carcinoma cells which caused re-activation of ERBB family receptors and intracellular signaling pathways. Blocking
ERBB receptor phosphorylation or ERK1/2 pathway activity using small-molecule inhibitors of
kinases for a short period of time following exposure (3 h) surprisingly protected
tumor cells from the toxic effects of ionizing radiation. Prolonged exposure (48-72 h) of
tumor cells to inhibition of
ERBB receptor/ERK1/2 function enhanced radiosensitivity. In addition to
ERBB receptor signaling, expression of activated forms of RAS family members and alterations in p53 mutational status are known to regulate radiosensitivity apparently independent of
ERBB receptor function; however, changes in RAS or p53 mutational status, in isogenic HCT116 cells, were also noted to modulate the expression of
ERBB receptors and
ERBB receptor paracrine
ligands. These alterations in receptor and
ligand expression correlated with changes in the ability of HCT116 cells to activate ERK1/2 and AKT after irradiation, and to survive radiation exposure. Collectively, our data in multiple human
carcinoma cell lines argues that
tumor cells are dynamic and rapidly adapt to any single therapeutic challenge, for example, radiation and/or genetic manipulation e.g. loss of activated RAS function, to maintain
tumor cell growth and viability.