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  • [Int J Radiat Oncol Biol Phys.] Ionizing radiation regulates vascular endothelial growth factor-A transcription in cultured human vascular endothelial cells via the PERK/eIF2α/ATF4 pathway.

    [Int J Radiat Oncol Biol Phys.] Ionizing radiation regulates vascular endothelial growth factor-A transcription in cultured human vascular endothelial cells via the PERK/eIF2α/ATF4 pathway.방사선에 의한 혈관내피세포의 반응조절기전연구

    KIRAMS / 김은주, 이현지, 임영빈*

  • 출처
    Int J Radiat Oncol Biol Phys.
  • 등재일
    2020 Mar 10.
  • 저널이슈번호
    pii: S0360-3016(20)30894-4. doi: 10.1;
  • 내용

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    Abstract
    PURPOSE:
    The delivery of high-dose hypofractionated radiation to a tumor induces vascular damage, but little is known about the responses of vascular endothelial cells to high-dose radiation. We examined whether high-dose irradiation alters VEGF signaling, which is a critical regulator of the functional integrity and viability of vascular endothelial cells.

    METHODS AND MATERIALS:
    Human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) were treated with 5, 10, 20, or 30 Gy ionizing radiation (IR). Expression values of VEGFA mRNA were analyzed by real-time PCR at 4 hours after irradiation and normalized to the average value of mock-irradiated HUVEC or HCAEC controls.

    RESULTS:
    Irradiation with doses higher than 10 Gy causes an acute increase in VEGFA transcript levels, which was accompanied by activation of the PERK/eIF2α/ATF4 pathway in the human vascular endothelial cells. ATF4 knockdown with siRNA completely prevented the IR-induced up-regulation of VEGFA transcripts, and chromatin immunoprecipitation assays demonstrated that ATF4 binding to the VEGFA locus was enriched in response to IR. Post-irradiation treatment with a intracellualr inhibitor of VEGF signaling significantly enhances high-dose IR-induced apoptosis in human vascular endothelial cells.

    CONCLUSION:
    Human vascular endothelial cells activate PERK/eIF2α/ATF4/VEGF signaling in response to high-dose IR to mitigate the apoptotic response. Thus, for cancer treatment, intracellular inhibitors of VEGF signaling could be employed to enhance stereotactic body radiation therapy-induced damage to the tumor vascular, which would augment tumor cell death.

     


    Author information

    Kim EJ1, Lee H1, Lee YJ1, Sonn JK2, Lim YB3.
    1
    Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
    2
    Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
    3
    Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea. Electronic address: yblim@kirams.re.kr.

     

    이달의 연구자 바로가기

  • 편집위원

    종양치료를 위한 high-dose hypofractionated radiation은 혈관손상을 유발하지만, 그 반응기전은 명확하지 않다. 본 연구는 혈관내피세포가 PERK/eIF2α/ATF4/VEGF 신호의 활성을 통해 방사선에 의한 세포사멸을 완화시킨다는 결과를 제시함으로써, 향후 VEGF 신호 억제를 통한 방사선치표 효율 향상의 기반을 제공했다.

    2020-04-27 17:00:17

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