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¹ Departments of Biochemistry,
² Medicine,
³ Radiation Oncology, and
⁴ Microbiology and Immunology, Virginia Commonwealth University, 401 College Street, Richmond, Virginia 23298, USA
⁵ IMBECU-CONICET, Mendoza, Argentina
⁶ Division of Gastroenterology/Hepatology, Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Pok Fu Lam Road, Hong Kong, China
⁷ Departments of Pathology, Neurosurgery and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York 10032, USA
⁸ Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, Gene Therapy Center, University of Alabama at Birmingham, Birmingham, 901 19th Street South, BMR2-502, Birmingham, Alabama 35294, USA

(Requests for offprints should be addressed to P Dent who is now at Department of Biochemistry, Massey Cancer Center, 401 College Street, Box 980058 Virginia Commonwealth University, Richmond, Virginia 23298-0058, USA; Email: pdent{at}hsc.vcu.edu)

This paper was presented at the 2nd Tenovus/AstraZeneca Workshop, Cardiff (2006). AstraZeneca supported the meeting and the Welsh School of Pharmacy, Cardiff University has supported the publication of these proceedings.

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.

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