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ELAS1-mediated inhibition of the cyclin G1–B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53

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Abstract

Radiation therapy (RT) is useful for selectively killing cancer cells. However, because high levels of ionizing radiation (IR) are toxic to normal cells, RT cannot be applied repeatedly to cancer patients. Therefore, novel chemicals that enhance the efficacy of chemoradiotherapy (CRT) would be valuable. Here, we report that ELAS1, a peptide corresponding to the protein phosphatase 2A (PP2A) association domain of cyclin G1 (CycG1), can enhance the efficacy of CRT. ELAS1 interacts with the PP2A B'γ-subunit and competitively inhibits association with CycG1, thereby preventing the PP2A holoenzyme from dephosphorylating target proteins, Mdm2 (pT218) and p53 (pS46), following DNA double-strand break (DSB) insults. Doxycycline (Dox)-induced overexpression of Myc-ELAS1 caused γ-irradiation to induce apoptosis in human osteosarcoma (U2OS) cells, at 1/10th the effective dosage of γ-irradiation required for apoptosis in Myc-vector-expressing cells; ELAS1 peptide incorporation into U2OS cells also showed similar apoptotic effects. Moreover, administration of DSB-inducing chemicals, camptothecin (CPT) or irinotecan, to Myc-ELAS1-expressing U2OS cells also induced efficient apoptosis with only 1/100th (CPT) or 1/5th (irinotecan) of the amounts of drugs required for this effect in Myc-vector-expressing cells. Taken together, ELAS1 may be important for the design of ELAS1-mimetic compounds to improve CRT efficacy.

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Acknowledgements

We thank Dr Patrick Hughes for critically reading the manuscript and Ms Yuki Ozaki for technical assistance. This work was supported by the Drug Discovery Gap Fund from Osaka University (to HN) and Grants-in-aid for Scientific Research (to HN) (No. 23370086) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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SO, SM and YN performed experiments and analyzed the data. SO, NY and HN conceived the experimental design and wrote the manuscript.

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Correspondence to H Nojima.

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Ohno, S., Naito, Y., Mukai, S. et al. ELAS1-mediated inhibition of the cyclin G1–B'γ interaction promotes cancer cell apoptosis via stabilization and activation of p53. Oncogene 34, 5983–5996 (2015). https://doi.org/10.1038/onc.2015.47

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