Acquired Radioresistance of Cancer and the AKT/GSK3β/cyclin D1 Overexpression Cycle

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概要

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• Fractionated radiotherapy (RT) is widely used in cancer therapy for its advantages in the preservation of normal tissues. However, repopulation of surviving tumor cells during fractionated RT limits the efficacy of RT. In fact, repopulating tumors often acquire radioresistance and this is the major cause of failure of RT. We have recently demonstrated that human tumor cells acquire radioresistance when exposed to fractionated radiation (FR) of X-rays every 12 hours for 1 month. The acquired radioresistance was associated with overexpression of cyclin D1, a result of a series of molecular changes; constitutive activation of DNA-PK and AKT with concomitant down-regulation of glycogen synthase kinase-3β (GSK3β) which results in suppression of cyclin D1 proteolysis. Aberrant cyclin D1 overexpression in S-phase induced DNA double strand breaks which activated DNA-PK and established the vicious cycle of cycling D1 overexpression. This overexpression of cyclin D1 is responsible for the radioresistance phenotype of long-term FR cells, since this phenotype was completely abrogated by treatment of FR cells by the API-2, an AKT inhibitor or by a Cdk4 inhibitor. Thus, targeting the AKT/GSK3β/cyclin D1/Cdk4 pathway can be an efficient modality to suppress acquired radioresistance of tumor cells. In this article, I overview the newly discovered molecular mechanisms underlying acquired radioresistance of tumor cells induced by FR, and propose a strategy for eradication of tumors using fractionated RT by overcoming tumor radioresistance.

• 2011-09-16

著者

• SHIMURA Tsutomu

  Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University

• Shimura Tsutomu

  Department Of Pathology Institute Of Development Aging And Cancer Tohoku University

関連論文

• The Modified High-Density Survival Assay is the Useful Tool to Predict the Effectiveness of Fractionated Radiation Exposure
• The Modified High-Density Survival Assay is the Useful Tool to Predict the Effectiveness of Fractionated Radiation Exposure
• Increased Frequencies of Gene and Chromosome Mutations after X-Irradiation in Mouse Embryonal Carcinoma Cells Transfected with the bcl-2 Gene
• The Effect of Caffeine on p53-Dependent Radioresponses in Undifferentiated Mouse Embryonal Carcinoma Cells after X-ray and UV-irradiations
• Clinically relevant radioresistant cells efficiently repair DNA double-strand breaks induced by X-rays
• Acquired Radioresistance of Cancer and the AKT/GSK3β/cyclin D1 Overexpression Cycle

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