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Kruppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage.

ABSTRACT: In response to gamma-radiation-induced DNA damage, organisms either activate cell cycle checkpoint and repair machinery or undergo apoptosis to eliminate damaged cells. Although previous studies indicated that the tumor suppressor p53 is critically involved in mediating both responses, how a cell decides which pathway to take is not well established. The zinc-finger-containing transcription factor, Krüppel-like factor 4 (KLF4), is a crucial mediator for the checkpoint functions of p53 after gamma-irradiation and does so by inhibiting the transition from the G(1) to S and G(2) to M phases of the cell cycle. Here, we determined the role of KLF4 in modulating the apoptotic response following gamma-irradiation. In three independent cell systems including colorectal cancer cells and mouse embryo fibroblasts in which expression of KLF4 could be manipulated, we observed that gamma-irradiated cells underwent apoptosis if KLF4 was absent. In the presence of KLF4, the degree of apoptosis was significantly reduced and cells resorted to checkpoint arrest. The mechanism by which KLF4 accomplished this antiapoptotic effect is by activating expression of the cell cycle arrest gene, p21(WAF1/CIP1), and by inhibiting the ability of p53 to transactivate expression of the proapoptotic gene, BAX. Results of our study illustrate an unexpected antiapoptotic function of KLF4, heretofore considered a tumor suppressor in colorectal cancer, and suggest that KLF4 may be an important determinant of cell fate following gamma-radiation-induced DNA damage.

SUBMITTER: Ghaleb AM

PROVIDER: S-EPMC2230633 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage.

Ghaleb A M AM Katz J P JP Kaestner K H KH Du J X JX Yang V W VW

Oncogene 20061002 16

In response to gamma-radiation-induced DNA damage, organisms either activate cell cycle checkpoint and repair machinery or undergo apoptosis to eliminate damaged cells. Although previous studies indicated that the tumor suppressor p53 is critically involved in mediating both responses, how a cell decides which pathway to take is not well established. The zinc-finger-containing transcription factor, Krüppel-like factor 4 (KLF4), is a crucial mediator for the checkpoint functions of p53 after gamm ...[more]

PMID: 17016435

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Project description:BackgroundTumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.MethodsThe efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).ResultsTTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the "skin sparing effect". Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.ConclusionsAdministration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.

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Kruppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage.

Publications

Krüppel-like factor 4 exhibits antiapoptotic activity following gamma-radiation-induced DNA damage.

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