Targeting DNA-PKcs and ATM with miR-101 Sensitizes Tumors to Radiation

Dan Yan,Chunhai Hao,Ping Wang,Xiangming Zhang,Yin-Yuan Mo,Jeffrey J Olson,Wooi Loon Ng,Zhaobin Zhang,Walter J Curran,Ya Wang,Hui Mao,Kerstin Borgmann

doi:10.1371/journal.pone.0011397

Dan Yan, Chunhai Hao + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0011397

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Abstract

BackgroundRadiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.Principal FindingsHere, we chose two genes: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3′- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo.ConclusionsThese data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy.

Highlights

Ionizing radiation (IR) kills cells by inducing DNA double strand breaks (DSBs), which is one of the major cancer therapy approaches
These results provide a new way for improving tumor radiotherapy
The human cell lines that are deficient in the DNAPK catalytic subunit (DNA-PKcs) or ATM are sensitive to IR because of the inefficient DNA DSB repair [1,2]

Summary

Introduction

Ionizing radiation (IR) kills cells by inducing DNA double strand breaks (DSBs), which is one of the major cancer therapy approaches. We were interested in testing the new hypothesis that targeting DNA-PKcs and ATM with one miRNA could sensitize tumor cells to IR. We found that miR-101 is one of the candidates because the duplex (miR-101* and miR-101) contains the matched sequences to the 39-UTR of DNA-PKcs or ATM mRNA (Figure 1A, B).

Results

Conclusion