Abstract
BackgroundRadiation therapy is one of the most effective therapeutic tools for brain metastasis. However, it is inevitable that some cancer cells become resistant to radiation. This study is focused on the identification of genes associated with radioresistance in metastatic brain tumor from lung cancer and the functional examination of the selected genes with regards to altered sensitivity of cancer cells to radiation.MethodsAfter establishing radioresistant cells from the xenograft model, we explored the significant transcriptional changes by performing DNA microarray profiling. Functional analyses in vitro and in vivo performed to validate the gene responsible for radioresistance.ResultsTranscriptional changes induced by radiation therapy are much more extensive in H460 cells than in PC14PE6 cells. The expression levels of TopBP1 and Claspin were increased in the cancer cells that survived radiation therapy. Depletion of TopBP1 or Claspin using shRNA showed an enhancement of sensitivity to radiation in radioresistant lung cancer cells (PC14PE6). Moreover, increased levels of TopBP1 or Claspin endowed cells a higher resistance to radiation. In xenograft models, the knock-down of TopBP1 or Claspin significantly prolonged the median survival time post radiation therapy.ConclusionsWe analyzed the gene expression profiles of the radiosensitive cells and the radioresistant cells to define a set of genes that may be involved in endowing lung cancer cells radioresistance post brain metastasis. Functional analyses indicated that the expression TopBP1 and Claspin positively affects the survival of cancer cells and thus negatively the xenograft metastasis model animals in response to radiation. These results show that TopBP1 and Claspin can be potential targets for the enhanced efficacy of radiotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-211) contains supplementary material, which is available to authorized users.
Highlights
Radiation therapy is one of the most effective therapeutic tools for brain metastasis
H460 cells have been less resistant to radiation, but cells from irradiated tumor cells (H460-5Gy and H460-10Gy) acquired radioresistance of over 90% of the survival rate (Figure 1C)
H460-10Gy cells were even more radioresistant than H460 and H460-5Gy. These results show that radiosensitive H460 cells acquired radioresistance in a dose dependent manner
Summary
Radiation therapy is one of the most effective therapeutic tools for brain metastasis. Even though multiple chemotherapeutic agents have been studied for treatment of metastatic brain tumors (MBTs), their clinical availability and effectiveness are still limited. In these circumstances, whole-brain radiation therapy has been used in the management of brain. Checkpoints aid maintaining genomic integrity and cell survival. These mechanisms can be used by cancer cells to evade apoptosis from DNA injury, resulting in acquiring resistance to irradiation [2,3]. Topoisomerase IIβ binding protein 1 (TopBP1) is an essential co-activator of ATR [6]. Claspin was identified as a Chk1-interacting protein and an important regulator of Chk activation [8,9]
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