Journal
ONCOGENE
Volume 29, Issue 34, Pages 4826-4837Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.238
Keywords
cyclin D1; AKT; fractionated-radiation; radioresistance; DNA-PK
Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare of Japan
- Interdisciplinary Research, Tohoku University
- [Start-up-20810003]
- [Wakate-B-21710054]
- Grants-in-Aid for Scientific Research [21310035] Funding Source: KAKEN
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Recurrence is frequently associated with the acquisition of radioresistance by tumors and resulting failures in radiotherapy. We report, in this study, that long-term fractionated radiation (FR) exposures conferred radioresistance to the human tumor cells, HepG2 and HeLa with cyclin D1 overexpression. A positive feedback loop was responsible for the cyclin D1 overexpression in which constitutively active AKT was involved. AKT is known to inactivate glycogen synthase kinase-3 beta (GSK3 beta), which is essential for the proteasomal degradation of cyclin D1. The resulting cyclin D1 overexpression led to the forced progression of S-phase with the induction of DNA double strand breaks. Cyclin D1-dependent DNA damage activated DNA-dependent protein kinase (DNA-PK), which in turn activated AKT and inactivated GSK3 beta, thus completing a positive feedback loop of cyclin D1 overproduction. Cyclin D1 overexpression led to the activation of DNA damage response (DDR) consisted of ataxia telangiectasia mutated (ATM)- and Chk1-dependent DNA damage checkpoint and homologous recombination repair (HRR). Long-term FR cells repaired radiation-induced DNA damage faster than non-FR cells. Thus, acquired radioresistance of long-term FR cells was the result of alterations in DDR mediated by cyclin D1 overexpression. Inhibition of the AKT/GSK3 beta/cyclin D1/Cdk4 pathway by the AKT inhibitor, Cdk4 inhibitor or cyclin D1 targeting small interfering RNA (siRNA) suppressed the radioresistance. Present observations give a mechanistic insight for acquired radioresistance of tumor cells by cyclin D1 overexpression, and provide novel therapeutic targets for recurrent radioresistant tumors. Oncogene (2010) 29, 4826-4837; doi:10.1038/onc.2010.238; published online 21 June 2010
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