Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Induction of Apoptosis by HDAC Inhibitor Trichostatin A through Activation of Caspases and NF-κB in Human Prostate Epithelial Cells.

인체 전립선 상피세포에서 HDAC 저해제 trichostatin A의 caspase 및 NF-κB의 활성화를 통한 apoptosis 유도

  • Park, Cheol (Department of Biological Sciences, Pusan National University) ;
  • Jin, Cheng-Yun (Department of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control (BK21 program), Dongeui University Graduate School) ;
  • Choi, Byung-Tae (Department of Anatomy, Graduate School of Oriental Medicine, Pusan National University) ;
  • Lee, Won-Ho (Department of Biological Sciences, Pusan National University) ;
  • Choi, Yung-Hyun (Department of Biochemistry, Dongeui University College of Oriental Medicine and Department of Biomaterial Control (BK21 program), Dongeui University Graduate School)
  • 박철 (부산대학교 자연과학대학 생물학과) ;
  • 김성윤 (동의대학교 한의과대학 생화학교실 및 동의대학교 대학원 바이오물질제어학과(BK21)) ;
  • 최병태 (부산대학교 한의학전문대학원 해부학교실) ;
  • 이원호 (부산대학교 자연과학대학 생물학과) ;
  • 최영현 (동의대학교 한의과대학 생화학교실 및 동의대학교 대학원 바이오물질제어학과(BK21))
  • Published : 2008.03.31
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Abstract

Histone deacetylases (HDACs) inhibitors have emerged as the accessory therapeutic agents for various human cancers, since they can block the activity of specific HDACs, restore the expression of some tumor suppressor genes and induce cell differentiation, cell cycle arrest and apoptosis in vitro and in vivo. In the present study, we investigated that the effect of trichostatin A (TSA), an HDAC inhibitor, on the cell growth and apoptosis, and its effect on the nuclear factor-kappaB $(NF-{\kappa}B)$ activity in 267B1 human prostate epithelial cells. Exposure of 267B1 cells to TSA resulted in growth inhibition and apoptosis induction in and dose-dependent manners as measured by fluorescence microscopy, agarose gel electrophoresis and flow cytometry analysis. TSA treatment inhibited the levels of IAP family members such as c-IAP-1 and c-IAP-2 and induced the proteolytic activation of caspase-3, -8 and -9, which were associated with concomitant degradation of poly (ADP-ribose)-polymerase, ${\beta}-catenin$ and laminin B proteins. The increase in apoptosis by TSA was connected with the translocation of $NF-{\kappa}B$ from cytosol to nucleus, increase of the DNA binding as well as promoter activity of $NF-{\kappa}B$, and degradation of cytosolic inhibitor of KappaB $(I{\kappa}B)-{\alpha}$ protein. We therefore concluded that TSA demonstrated anti-proliferative and apoptosis-inducing effects on 267B1 cells in vitro, and that the activation of caspases and $NF-{\kappa}B$ may play important roles in its mechanism of action. Although further studies are needed, these findings provided important insights into the possible molecular mechanisms of the anti-cancer activity of TSA.

본 연구에서는 인체전립선 상피세포인 267B1 세포에서 HDAC 저해제인 TSA에 의한 증식억제가 apoptosis 유도에 의한 것임을 제시하였다. 이러한 TSA에 의한 267B1 세포의 apoptosis에는 c-IAP-1 및 c-IAP-2와 같은 IAP family의 발현감소가 동반되었으나 Bax 및 Bcl-2와 같은 Bcl-2 family의 발현에는 큰 변화가 없었다. 그리고 TSA에 의한 267Bl 세포의 apoptosis는 caspase의 활성에 의한 표적 단백질들의 분해와 연관성이 있었다. 또한 TSA에 의한 apoptosis 유도에서 $NF-{\kappa}B$의 활성이 증가된다는 것을 세포질에서 $NF-{\kappa}B$의 핵 내로의 이동에 따른 전사활성의 증가 현상에 의한 것임을 다양한 방법으로 제시하였다. 본 연구의 결과는 TSA와 같은 HDAC 저해제에 의한 apoptosis 유도에는 $NF-{\kappa}B$의 활성 증가가 동반될 수 있음을 보여주는 결과로서 HDAC 저해제의 항암활성에 대한 $NF-{\kappa}B$의 새로운 역할 가능성을 제시하여 주는 것으로서 이에 관한 추가적인 연구의 필요성을 제시하였다.

Keywords

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