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Reviews

Radiation-induced cell signaling: inside-out and outside-in

Departments of ¹ Biochemistry, ² Medicine, and ³ Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia; ⁴ Departments of Pathology, Neurosurgery and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; and ⁵ Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Paul Dent, Department of Biochemistry, Virginia Commonwealth University, 401 College Street, Box 980035, Richmond, VA 23298. Phone: 804-628-0861; Fax: 804-828-6042. E-mail: pdent{at}vcu.edu

Exposure of tumor cells to clinically relevant doses of ionizing radiation causes DNA damage as well as mitochondria-dependent generation of reactive oxygen species. DNA damage causes activation of ataxia telangiectasia mutated and ataxia telangiectasia mutated and Rad3-related protein, which induce cell cycle checkpoints and also modulate the activation of prosurvival and proapoptotic signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH₂-terminal kinase 1/2, respectively. Radiation causes a rapid reactive oxygen species–dependent activation of ERBB family and other tyrosine kinases, leading to activation of RAS proteins and multiple protective downstream signaling pathways (e.g., AKT and ERK1/2), which alter transcription factor function and the apoptotic threshold of cells. The initial radiation-induced activation of ERK1/2 can promote the cleavage and release of paracrine ligands, which cause a temporally delayed reactivation of receptors and intracellular signaling pathways in irradiated and unirradiated bystander cells. Hence, signals from within the cell can promote activation of membrane-associated receptors, which signal back into the cytosol: signaling from inside the cell outward to receptors and then inward again via kinase pathways. However, cytosolic signaling can also cause release of membrane-associated paracrine factors, and thus, paracrine signals from outside of the cell can promote activation of growth factor receptors: signaling from the outside inward. The ultimate consequence of these signaling events after multiple exposures may be to reprogram the irradiated and affected bystander cells in terms of their expression levels of growth-regulatory and cell survival proteins, resulting in altered mitogenic rates and thresholds at which genotoxic stresses cause cell death. Inhibition of signaling in one and/or multiple survival pathways enhances radiosensitivity. Prolonged inhibition of any one of these pathways, however, gives rise to lineages of cells, which have become resistant to the inhibitor drug, by evolutionary selection for the clonal outgrowth of cells with point mutations in the specific targeted protein that make the target protein drug resistant or by the reprogramming of multiple signaling processes within all cells, to maintain viability. Thus, tumor cells are dynamic with respect to their reliance on specific cell signaling pathways to exist and rapidly adapt to repeated toxic challenges in an attempt to maintain tumor cell survival. [Mol Cancer Ther 2007;6(3):789–801]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ S. Golding et al. ERK positively regulates ATM, homologous recombination repair and the DNA damage response, submitted for publication.

⁷ A. Khalil et al. ATM-dependent and -independent ERK signaling in response to DNA double-strand breaks, submitted for publication.

Received 9/26/06; revised 10/26/06; accepted 12/13/06.

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