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PNAS 101 (37): 13495-13500

Copyright © 2004 by the National Academy of Sciences.


Targeted cytoplasmic irradiation induces bystander responses

Chunlin Shao, Melvyn Folkard, Barry D. Michael, and Kevin M. Prise *

Gray Cancer Institute, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, United Kingdom

Edited by Richard B. Setlow, Brookhaven National Laboratory, Upton, NY, and approved August 4, 2004

Received for publication July 8, 2004.

Abstract: The observation of radiation-induced bystander responses, in which cells respond to their neighbors being irradiated, has important implications for understanding mechanisms of radiation action particularly after low-dose exposure. Much of this questions the current dogma of direct DNA damage driving response in irradiated systems. In this study, we have used a charged-particle microbeam to target individual helium ions (3He2+) to individual cells within a population of radioresistant glioma cells cultured alone or in coculture with primary human fibroblasts. We found that even when a single cell within the glioma population was precisely traversed through its cytoplasm with one 3He2+ ion, bystander responses were induced in the neighboring nonirradiated glioma or fibroblasts so that the yield of micronuclei was increased by 36% for the glioma population and 78% for the bystander fibroblast population. Importantly, the yield of bystander-induced micronuclei was independent of whether the cytoplasm or nucleus of a cell was targeted. The bystander responses were fully eliminated when the populations were treated with 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide or filipin, which scavenge nitric oxide (NO) and disrupt membrane rafts, respectively. By using the probe 4-amino-5-methylamino-2',7'-difluorofluorescein, it was found that the NO level in the glioma population was increased by 15% after 1 or 10 cytoplasmic traversals, and this NO production was inhibited by filipin. This finding shows that direct DNA damage is not required for switching on of important cell-signaling mechanisms after low-dose irradiation and that, under these conditions, the whole cell should be considered a sensor of radiation exposure.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: NO, nitric oxide; MN, micronucleus; c-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; GEMs, glycosphingolipid-enriched membrane microdomains.

* To whom correspondence should be addressed. E-mail: prise{at}

© 2004 by The National Academy of Sciences of the USA

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