Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Inhibitory Effects of Type IV Collagenase by Disulfiram

Disulfiram에 의한 type IV collagenase 저해효과

  • Sin, Doo-Il (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Park, Jae-Bok (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Park, Kwan-Kyu (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Cho, Chang-Ho (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Oh, Hoon-Kyu (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Choi, Chang-Hyuk (Department of Orthopedic Surgery, Catholic University of Daegu School of Medicine) ;
  • Cho, Hyun-Ji (Department of Pathology, Catholic University of Daegu School of Medicine) ;
  • Chang, Young-Chae (Department of Pathology, Catholic University of Daegu School of Medicine)
  • 신두일 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 박재복 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 박관규 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 조창호 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 오훈규 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 최창혁 (대구가톨릭대학교 의과대학 정형외과학교실) ;
  • 조현지 (대구가톨릭대학교 의과대학 병리학교실) ;
  • 장영채 (대구가톨릭대학교 의과대학 병리학교실)
  • Published : 2006.10.01
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Abstract

The cancer cells, characterized by local invasion and distant metastasis, are very dependant on extracellular matrix. The expression of matrix metalloproteinases (MMPs) has been implicated in the invasion and metastasis of cancer cells. Among the human MMPs, matirx metalloproteinase-2 (MMP-2) and matrix metalloproteinse-9 (MMP-9) are key enzymes that degrade type IV collagen of the matrix. Here, we studied the effect of disulfiram, an anti-tumor compound, on the suppression of the tumor invasion and the activity of MMP-2, MMP-9 in human osteosarcoma cells (U2OS). Disulfiram had the type IV collagenase inhibitory activity, the effect of inhibition of gene and protein expression, and these inhibitions were responsible for blocking invasion through cell mediated and non-cell mediated pathways. In conclusion, disulfiram inhibited expression of MMP-2 and MMP-9, and regulated the invasion of U2OS, Caki-1 and Caski. These observations raise the possibility of clinical therapeutic applications for disulfiram used as a potential inhibitor of cancer invasion.

기질의 침윤과 전이를 특징으로 하는 악성종양 세포는 세포외 기질이나 기저막에 의존적으로 작용한다. 세포외 기질을 분해하는 효소인 matrix metalloproteinase (MMP) 계들의 발현 및 활성증가는 대부분의 악성종양세포에서 전이와 침윤을 촉진시킨다. MMP family 가운데 특히 type IV collagenase 활성을 지닌 MMP-2와 MMP-9은 세포외기질의 중요한 구성분인 collagen, fibronectin을 분해하는 특성을 가지며 암 전이를 용이하게 하는 주요한 효소로 잘 알려져 있다. 본 연구에서는 항암후보물질인 disulfiram이 골 육종 (U20S), 신장암 (Caki-1) 및 자궁암 (Caski) 세포에서 MMP-2와 MMP-9의 효소활성 및 발현억제에 대해 조사하였다. MTT assay를 이용하여 disulfiram에 대한 암세포 viability 실험에서는 disulfiram이 암세포의 viability를 저해하였다. 또한 zymography, western blot 및 RT-PCR 등을 이용한 type IV collagenase의 활성 및 발현 실험에서 disulfiram은 type IV collagenase의 활성을 비롯하여 단백질 및 mRNA 발현을 억제시키는 것을 확인하였다. 따라서 disulfiram이 MMP-2와 MMP-9의 활성 및 발현 억제 기전을 통하여 골 육종, 신장암 및 자궁경부암 세포의 작용을 억제한다는 연구 결과는 disulfiram이 각종 악성종양의 침윤과 전이를 억제 또는 방지하기 위한 치료물질로서 임상에서 활용할 수 있는 가능성을 보여준다.

Keywords

References

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