Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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HMGB1 Switches Alkylating DNA Damage-Induced Apoptosis to Necrosis

HMGB1에 의한 alkylating DNA 손상에 의해 유도된 세포사멸의 세포괴사로의 전환

  • Lee, Su-Yeon (Department of Molecular Biology, College of Natural Sciences) ;
  • Jeong, Eui-Kyong (Department of Molecular Biology, College of Natural Sciences) ;
  • Jeon, Hyun-Min (Department of Molecular Biology, College of Natural Sciences) ;
  • Ju, Min-Kyung (Department of Molecular Biology, College of Natural Sciences) ;
  • Kim, Cho-Hee (Department of Molecular Biology, College of Natural Sciences) ;
  • Park, Hye-Gyeong (Nanobiotechnology Center, Pusan National University) ;
  • Kang, Ho-Sung (Department of Molecular Biology, College of Natural Sciences)
  • 이수연 (부산대학교 자연과학대학 분자생물학과) ;
  • 정의경 (부산대학교 자연과학대학 분자생물학과) ;
  • 전현민 (부산대학교 자연과학대학 분자생물학과) ;
  • 주민경 (부산대학교 자연과학대학 분자생물학과) ;
  • 김초희 (부산대학교 자연과학대학 분자생물학과) ;
  • 박혜경 (한국나노바이오테크놀러지센터) ;
  • 강호성 (부산대학교 자연과학대학 분자생물학과)
  • Received : 2011.05.12
  • Accepted : 2011.07.04
  • Published : 2011.07.30
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Abstract

Necrosis is characterized by the cell membrane rupture and release of the cellular contents, including high-mobility group box 1 protein (HMGB1), into the extracellular microenvironment. HMGB1 acts as a transcriptional regulator in nuclei, but exerts a pro-inflammatory and tumor-promoting cytokine activity when released into the extracellular space. Its overexpression is associated with tumor progression and chemoresistance. Thus, HMGB1 acts as a clinically important molecule in tumor biology. In this study, we examined whether HMGB1 affects cell death induced by anti-cancer drugs. Here we show that HMGB1 prevented cisplatin (alkylating agent)-induced apoptosis and switched the cell fate to necrosis in MCF-7, MDA-MB231, and MDA-MB361 cells. Similar apoptosis-to-necrosis switch effects of HMGB1 were observed in cells treated with 4-HC, another alkylating agent. In contrast, HMGB1 did not exert any significant effects on docetaxel (DOC)-induced apoptosis in MCF-7 cells. We also show that cisplatin-induced apoptosis was switched to necrosis in MCF-7 multicellular tumor spheroids (MTS) that were cultured for 8 days and had necrotic cores, but DOC-induced apoptosis was prevented without the apoptosis-to-necrosis switch. Finally, the levels of RAGE, a receptor of HMGB1, were increased with extended culture of MTS. These findings demonstrate that HMGB1 switches alkylating agent-induced apoptosis to necrosis, suggesting that the strategy to prevent necrosis occurring as an undesirable action of alkylating agent-based chemotherapy should be delineated to improve the efficacy of chemotherapy for cancer.

세포괴사는 세포막의 파열, HMGB1을 포함한 세포 내용물의 세포외부로의 방출 등을 수반하는 세포죽음이다. HMGB1은 핵 단백질로 전사조절자로 작용하지만 세포괴사에 의해 세포 밖으로 방출되면 염증을 유발하고 암을 촉진하는 cytokine으로 작용한다. HMGB1의 과발현은 암 발생 및 항암제 저항과 밀접한 연관성을 가지고 있지만, 그 기작에 대한 연구는 미흡한 실정이다. 본 연구에서는, HMGB1이 항암제에 의한 세포 죽음에 미치는 영향을 조사하였다. 그 결과, HMGB1은 MCF-7, MDA-MB231, MDA-MB361 세포에서 cisplatin에 의한 세포사멸을 억제하고 세포운명을 세포괴사로 바꾼다는 사실을 확인하였다. HMGB1의 세포사멸-세포괴사 전환 작용을 4-HC를 처리한 세포에서도 관찰되었다. 그러나, HMGB1은 docetaxel (DOC)에 의한 세포사멸에는 영향을 주지 않음을 확인하였다. MTS를 이용하여 항암제에 의한 세포 죽음에 미치는 영향을 조사한 결과, necrotic core가 형성된 8일째 MCF-7 MTS에서 cisplatin에 의한 세포사멸이 세포괴사로 바뀌는 반면, DOC에 의한 세포사멸은 세포괴사로 전환되지 않는 것을 확인하였다. 또한 spheroid에서 HMGB1 receptor인 RAGE의 발현이 증가함을 확인하였다. 이러한 결과를 통해, HMGB1이 alkylating agent에 의한 세포사멸을 세포괴사로 전환시킴을 알 수 있었다. 따라서, alkylating agent에 의한 항암제 효능을 나타내기 위해선, 이들 항암제의 부작용 즉 세포괴사를 억제하는 전략이 필요한 것으로 생각된다.

Keywords

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