Abstract
Ionizing radiation (IR) induces a DNA damage response that includes activation of cell cycle checkpoints, leading to cell cycle arrest. In addition, IR enhances cell invasiveness of glioblastoma cells, among other tumor cell types. Using RNA interference, we found that the protein kinase MRK, previously implicated in the DNA damage response to IR, also inhibits IR-induced cell migration and invasion of glioblastoma cells. We showed that MRK activation by IR requires the checkpoint protein Nbs1 and that Nbs1 is also required for IR-stimulated migration. In addition, we show that MRK acts upstream of Chk2 and that Chk2 is also required for IR-stimulated migration and invasion. Thus, we have identified Nbs1, MRK, and Chk2 as elements of a novel signaling pathway that mediates IR-stimulated cell migration and invasion. Interestingly, we found that inhibition of cell cycle progression, either with the CDK1/2 inhibitor CGP74514A or by downregulation of the CDC25A protein phosphatase, restores IR-induced migration and invasion in cells depleted of MRK or Chk2. These data indicate that cell cycle progression, at least in the context of IR, exerts a negative control on the invasive properties of glioblastoma cells and that checkpoint proteins mediate IR-induced invasive behavior by controlling cell cycle arrest.
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Acknowledgments
This study was supported by the NCI Grant CA100747 to R.R., funds from the Project to Cure Foundation to M. S., the Little Louie Foundation, the Bradley Zankel Foundation, Inc. to R.R. and institutional funds from the Feinstein Institute. I.V. was supported by a St. Baldrick’s Foundation Childhood Cancer Research Fellowship award. We also would like to thank Dr. Jeff Lipton and Dr. Mark Atlas (Cohen Children’s Medical Center of New York) for stimulating discussions and support.
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The authors declare that they have no conflict of interest.
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Vanan, I., Dong, Z., Tosti, E. et al. Role of a DNA Damage Checkpoint Pathway in Ionizing Radiation-Induced Glioblastoma Cell Migration and Invasion. Cell Mol Neurobiol 32, 1199–1208 (2012). https://doi.org/10.1007/s10571-012-9846-y
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DOI: https://doi.org/10.1007/s10571-012-9846-y