Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3Β- mediated cyclin D1 overexpression

T. Shimura, S. Kakuda, Y. Ochiai, H. Nakagawa, Y. Kuwahara, Y. Takai, J. Kobayashi, K. Komatsu, M. Fukumoto

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)

Abstract

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-3Β (GSK3Β), 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 GSK3Β, 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/GSK3Β/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.

Original languageEnglish
Pages (from-to)4826-4837
Number of pages12
JournalOncogene
Volume29
Issue number34
DOIs
Publication statusPublished - 2010 Aug 26

Keywords

  • AKT
  • DNA-PK
  • cyclin D1
  • fractionated-radiation
  • radioresistance

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3Β- mediated cyclin D1 overexpression'. Together they form a unique fingerprint.

Cite this