Radiotherapy-induced signal transduction

Adly Yacoub, Anna Miller, Ruben W. Caron, Liang Qiao, David A. Curiel, Paul B. Fisher, Michael P. Hagan, Steven Grant, Paul Dent

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25 Scopus citations


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.

Original languageEnglish
Pages (from-to)S99-S114
JournalEndocrine-Related Cancer
Issue numberSUPPL. 1
StatePublished - Dec 1 2006
Externally publishedYes

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    Yacoub, A., Miller, A., Caron, R. W., Qiao, L., Curiel, D. A., Fisher, P. B., Hagan, M. P., Grant, S., & Dent, P. (2006). Radiotherapy-induced signal transduction. Endocrine-Related Cancer, 13(SUPPL. 1), S99-S114.