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  • [BMC Cancer.] Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells.

    인천대, 연세의대 / 조한희, 이미수*, 윤미진*

  • 출처
    BMC Cancer.
  • 등재일
    2020 Apr 19
  • 저널이슈번호
    20(1):332. doi: 10.1186/s12885-020-06822-4.
  • 내용

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    Abstract
    BACKGROUND:
    Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib.

    METHODS:
    To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays.

    RESULTS:
    SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells.

    CONCLUSIONS:
    Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

     

     


    Author information

    Jo H1,2, Park Y1, Kim T3, Kim J1, Lee JS1, Kim SY2, Chung JI2, Ko HY2, Pyun JC3, Kim KS4, Lee M5, Yun M6.
    1
    Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea.
    2
    Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea.
    3
    Department of Materials Science and Engineering, Yonsei University, Seoul, South Korea.
    4
    Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
    5
    Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea. misulee@inu.ac.kr.
    6
    Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea. YUNMIJIN@yuhs.ac.

  • 키워드
    Anti-tumor effect; CDK4/6 inhibitor; Drug sensitivity; Hepatocellular carcinoma; SIRT3; Sorafenib
  • 연구소개
    다양한 종양에서 tumor suppressor gene으로서 역할을 하는 SIRT3가 18F-FDG uptake가 높은 간암환자에서 발현양이 현저히 감소 되었으며, 간암의 유일한 치료제인 sorafenib 약물 민감도에 영향을 미치는 것을 본 연구에서 확인하였음. 또한, CDK4/6 억제제를 통해서 SIRT3 발현을 증가시킴으로써 간암세포에서 sorafenib 약물 민감도를 증가시키는 결과를 봄. 따라서, 본 연구를 통해 SIRT3 발현 조절 약물이 sorafenib 효과 증진시킬 수 있는 병합치료 가능성이 있음을 보여주었음.
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