Targeting the AKT/GSK3{beta}/Cyclin D1/Cdk4 Survival Signaling Pathway for Eradication of Tumor Radioresistance Acquired by Fractionated Radiotherapy

Journal Article · Wed Jun 01 00:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.12.065· OSTI ID:21491775

Shimura, Tsutomu; Kakuda, Satoshi; Ochiai, Yasushi; Kuwahara, Yoshikazu ^[1]; Takai, Yoshihiro ^[2]; Fukumoto, Manabu ^[1]

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1. Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai (Japan)
2. Department of Radiology and Radiation Oncology, Hirosaki University School of Medicine, Hirosaki (Japan)

Purpose: Radioresistance is a major cause of treatment failure of radiotherapy (RT) in human cancer. We have recently revealed that acquired radioresistance of tumor cells induced by fractionated radiation is attributable to cyclin D1 overexpression as a consequence of the downregulation of GSK3{beta}-dependent cyclin D1 proteolysis mediated by a constitutively activated serine-threonine kinase, AKT. This prompted us to hypothesize that targeting the AKT/GSK3{beta}/cyclin D1 pathway may improve fractionated RT by suppressing acquired radioresistance of tumor cells. Methods and Materials: Two human tumor cell lines with acquired radioresistance were exposed to X-rays after incubation with either an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2), or a Cdk4 inhibitor (Cdk4-I). Cells were then subjected to immunoblotting, clonogenic survival assay, cell growth analysis, and cell death analysis with TUNEL and annexin V staining. In vivo radiosensitivity was assessed by growth of human tumors xenografted into nude mice. Results: Treatment with API-2 resulted in downregulation of cyclin D1 expression in cells with acquired radioresistance. Cellular radioresistance disappeared completely both in vitro and in vivo with accompanying apoptosis when treated with API-2. Furthermore, inhibition of cyclin D1/Cdk4 by Cdk4-I was sufficient for abolishing radioresistance. Treatment with either API-2 or Cdk4-I was also effective in suppressing resistance to cis-platinum (II)-diamine-dichloride in the cells with acquired radioresistance. Interestingly, the radiosensitizing effect of API-2 was canceled by overexpression of cyclin D1 whereas Cdk4-I was still able to sensitize cells with cyclin D1 overexpression. Conclusion: Cyclin D1/Cdk4 is a critical target of the AKT survival signaling pathway responsible for tumor radioresistance. Targeting the AKT/GSK3{beta}/cyclin D1/Cdk4 pathway would provide a novel approach to improve fractionated RT and would have an impact on tumor eradication in combination with chemotherapy.

• OSTI ID: 21491775
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 80, Issue 2; Other Information: DOI: 10.1016/j.ijrobp.2010.12.065; PII: S0360-3016(11)00070-8; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
APOPTOSIS
FRACTIONATED IRRADIATION
IN VITRO
IN VIVO
NEOPLASMS
PLATINUM COMPLEXES
PROTEOLYSIS
RADIOSENSITIVITY
RADIOTHERAPY
SERINE
THREONINE
TUMOR CELLS
X RADIATION
AMINO ACIDS
ANIMAL CELLS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
COMPLEXES
DECOMPOSITION
DISEASES
ELECTROMAGNETIC RADIATION
HYDROXY ACIDS
IONIZING RADIATIONS
IRRADIATION
MEDICINE
NUCLEAR MEDICINE
ORGANIC ACIDS
ORGANIC COMPOUNDS
RADIATIONS
RADIOLOGY
SENSITIVITY
THERAPY
TRANSITION ELEMENT COMPLEXES