Journal Article

Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3β-mediated cyclin D1 overexpression

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

2010

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/45/612/1223 / 631/67/1059/2326 / 631/80/86 / 692/699/67 / AKT protein / Apoptosis / Ataxia telangiectasia / Ataxia telangiectasia mutated protein / Biological and medical sciences / Cancer cells / Cell Biology / Cell physiology / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / CHK1 protein / Cyclin D1 / Cyclin-dependent kinase 4 / Cyclins / Deoxyribonucleic acid / DNA / DNA damage / DNA-dependent protein kinase / Feedback / Fundamental and applied biological sciences. Psychology / Gene expression / Genetic aspects / Glycogen / Glycogen synthase kinase 3 / Health aspects / Homologous recombination / Homologous recombination repair / Human Genetics / Internal Medicine / Kinases / Medicine / Medicine & Public Health / Methods / Molecular and cellular biology / Oncology / original-article / Physiological aspects / Properties / Proteasomes / Radiation / Radiation therapy / Radioresistance / Radiotherapy / siRNA / Therapeutic targets / Tumor cells / Tumors