Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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The Mechanism of Proteasome Inhibitor-Induced Apoptosis in Lung Cancer Cells

폐암 세포에서 Proteasome Inhibitor에 의한 Apoptosis의 기전

  • Kim, Cheol Hyeon (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Lee, Kyoung-Hee (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Lee, Choon-Taek (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Kim, Young Whan (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Han, Sung Koo (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Shim, Young Soo (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University) ;
  • Yoo, Chul Gyu (Division of Pulmonary and Critical care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul National University)
  • 김철현 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 이경희 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 이춘택 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 김영환 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 한성구 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 심영수 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소) ;
  • 유철규 (서울대학교 의과대학 내과학교실 및 의학연구원 폐연구소)
  • Published : 2003.04.30
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Abstract

Background : Proteasome inhibitors can promote either cell survival or programmed cell death, depending on both the specific type and proliferative status of the cell. However, it is not well known whether inhibition of proteasome activity is related to apoptosis in lung cancer cells. In addition, the exact mechanisms responsible for apoptosis induced by proteasome inhibition are not well understood. In the present study, we have examined the effect of proteasome inhibition on lung cancer cells and tried to test the mechanisms that may be associated with the apoptosis of these cells. Methods : We examined the effect of proteasome inhibition with MG132 or PS-341 on cell survival in A549 and NCI-H157 lung cancer cells using MTT assay, and analyzed the cleavage of PARP by Western blot analysis to find evidence of apoptosis. Next, we evaluated the activation of caspase 3 by Western blot analysis and the activity of JNK by immunocomplex kinase assay. We also examined the changes in anti-apoptotic pathways like ERK and cIAP1 by Western blot analysis after inhibition of proteasome function. Results : We demonstrated that MG132 reduced cell survival by inducing apoptosis in A549 and NCI-H157 cells. Proteasome inhibition with MG132 or PS-341 was associated with activation of caspase 3 and JNK, reduced expression of activated ERK, and downregulation of cIAP1. Conclusion : Apoptosis induced by proteasome inhibition may be associated with the activation of pro-apoptotic pathways like caspase 3 and JNK and the inactivation of anti-apoptotic pathways in lung cancer cells.

연구배경 : Proteasome 억제가 세포의 apoptosis에 미치는 영향은 세포 종류에 따라 차이를 보이고 있다. 그러나 아직까지 폐암 세포에서 proteasome 억제가 미치는 효과 및 그 기전에 관해서는 확실하게 규명되어 있지 못한 상태이다. 본 연구에서는 폐암 세포주에서 proteasome 억제에 의한 apoptosis의 유도 유무를 관찰하고, 그 기전을 규명하고자 하였다. 방 법 : 폐암 세포주인 A549와 NCI-H157 세포에 proteasome 억제제인 MG132와 PS-341을 투여하고 세포의 생존율을 MTT 분석으로 평가하였고, apoptosis 유무를 PARP 단백에 대한 Western 분석으로 확인하였다. Proteasome 억제가 caspase 3와 JNK의 활성화에 미치는 효과를 각각 Western 분석과 immunocomplex kinase 분석으로 평가하였다. Proteasome 억제제를 투여하고 항 apoptosis 경로인 ERK와 cIAP1에 미치는 효과를 Western 분석으로 평가하였다. 결 과 : A549와 NCI-H157 세포에 MG132를 투여하였을 때, 세포생존율의 감소가 관찰되었고, 이는 apoptosis의 유도에 의한 것으로 확인되었다. MG132와 PS-341 처치로 caspase 3와 JNK가 활성화되었다. 반면에 활성화된 ERK의 발현과 cIAP1의 발현은 감소하였다. 결 론 : 폐암 세포에서 proteasome 억제에 의한 apoptosis에는 caspase 3, JNK와 같은 apoptosis 유도 경로의 활성화와 함께 항 apoptosis 경로의 억제가 관여할 것으로 생각된다.

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