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Does metabolic radiolabeling stimulate the stress response? Gene expression profiling reveals differential cellular responses to internal beta vs. external gamma radiation

NICHOLAS F. MARKO^*,1, PAUL B. DIEFFENBACH^*,1, GAI YAN^*, SUSAN CERYAK, ROGER W. HOWELL, TIMOTHY A. MCCAFFREY^* and VALERIE W. HU^*,2

Departments of
^* Biochemistry and Molecular Biology and
Pharmacology The George Washington University School of Medicine, Washington, DC, USA; and
Department of Radiology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA

²Correspondence: Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, 2300 Eye St., N.W., Washington, DC 20037, USA. E-mail: bcmvwh{at}gwumc.edu

DNA microarray analyses were used to investigate the effect of cell-incorporated ³⁵S-methionine on human colorectal carcinoma cells. This ß-radiation-induced gene expression profile was compared with that induced by external -radiation. The extent of DNA fragmentation was used as a biomarker to determine the external dose that was bioequivalent to that received by cells incubated in medium containing ³⁵S-methionine. Studies showed that ³⁵S-methionine at 100 µCi/mL induced a much more robust transcriptional response than -radiation (2000 cGy) when evaluated 2 h after the labeling or irradiation period. The cellular response to internal ß-radiation was greater not only with respect to the number of genes induced, but also with respect to the level of gene induction. Not surprisingly, the induced genes overlapped with the set of -responsive genes. However, a distinct ß-gene induction profile that included a large number of cell adhesion proteins was also observed. Taken together, these studies demonstrate that metabolic incorporation of a low energy ß-emitter, such as ³⁵S-methionine, can globally influence a diverse set of cellular activities that can, in turn, affect the outcome of many experiments by altering the cell cycle, metabolic, signaling, or redox status (set point) of the cell. Additional studies of the mechanism of ß-induced proliferation arrest and cell death and of the significance of its differential gene induction/repression profile in comparison to pulsed -irradiation may lead to new insights into the ways in which ionizing radiation can interact with cells.—Marko, N. F., Dieffenbach, P. B., Yan, G., Ceryak, S., Howell, R. W., McCaffrey, T. A., Hu, V. W. Does metabolic radiolabeling stimulate the stress response? Gene expression profiling reveals differential cellular responses to internal beta vs. external gamma radiation.

Key Words: DNA microarray • DNA damage • ionizing radiation • radioisotopes • sulfur-35 methionine

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