생명과학회지 (Journal of Life Science)

  • 제22권8호
  • /
  • Pages.1018-1023
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  • 2012
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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Snail의 Akt/PKB의 활성화와 p53의 downregulation를 통한 5-FU-induced apoptosis의 necrosis로의 전환

Snail Switches 5-FU-induced Apoptosis to Necrosis through Akt/PKB Activation and p53 Down-regulation

  • 이수연 (부산대학교 자연과학대학 분자생물학과) ;
  • 전현민 (부산대학교 자연과학대학 분자생물학과) ;
  • 주민경 (부산대학교 자연과학대학 분자생물학과) ;
  • 김초희 (부산대학교 자연과학대학 분자생물학과) ;
  • 정의경 (부산대학교 자연과학대학 분자생물학과) ;
  • 박혜경 (부산대학교 나노바이오테크놀러지 센터) ;
  • 강호성 (부산대학교 자연과학대학 분자생물학과)
  • Lee, Su-Yeon (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Jeon, Hyun-Min (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Ju, Min-Kyung (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Kim, Cho-Hee (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Jeong, Eui-Kyong (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Park, Hye-Gyeong (Nanobiotechnology Center, Pusan National University) ;
  • Kang, Ho-Sung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
  • 투고 : 2012.07.09
  • 심사 : 2012.08.16
  • 발행 : 2012.08.30
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초록

Snail은 E-cadherin 발현을 직접 억제하는 zinc finger transcription factor로서, 암세포의 invasion과 metastasis를 촉진시키는 epithelial-mesenchymal transition (EMT)를 유발한다. 또한 Snail은 세포사멸 자극과 세포 생존물질의 제거로 인한 세포사멸에 대해 저항성을 나타낸다. 그러나 이에 대한 분자기작은 잘 알려져 있지 않다. 본 연구에서는 가장 널리 사용되는 항암제 중의 하나인 5-fluorouracil (5-FU)에 의한 세포사멸에 대한 Snail의 저항성 기작에 대하여 조사하였다. MCF-7 #5 세포주에 doxycycline (DOX)을 처리하여 Snail을 과발현시킨 세포에서 5-FU에 의한 세포사멸이 억제되고 세포괴사가 일어남을 확인하였다. DOX 처리 및 Snail expression vectors인 pCR3.1-Snail-Flg와 phosphorylation-resistant mutant Snail vector인 pCR3.1-S104, 107A Snail-Flg을 이용하여 Snail을 과발현 시킨 경우 ERK1/2의 활성에는 영향을 주지 않는 반면 PTEN 발현억제 및 불활성화, 그리고 Akt/PKB 활성화가 유도됨을 관찰하였다. 또한, Snail은 5-FU에 의한 p53의 발현을 억제한다는 사실을 확인하였다. 따라서 Snail은 prosurvival kinase인 Akt/PKB의 활성화와 p53 억제를 통해 5-FU에 의한 세포사멸을 세포괴사로 전환하는 것으로 생각된다.

Snail is a zinc finger transcription factor that induces epithelial-to-mesenchymal transition (EMT), which promotes tumor invasion and metastasis by repressing E-cadherin expression. In addition, Snail restricts the cellular apoptotic response to apoptotic stimuli or survival factor withdrawal; however, its molecular mechanism remains largely unknown. In this study, we have investigated the mechanism underlying Snail-mediated chemoresistance to 5-fluorouracil (5-FU), one of the most widely used anti-cancer drugs. When Snail was overexpressed by doxycycline (DOX) in MCF-7 #5 cells, it inhibited 5-FU-induced apoptotic cell death and switched the cell death mode to necrosis. Snail expression, either by DOX treatment in MCF-7 #5 cells or by the transfection of Snail expression vectors pCR3.1-Snail-Flg, phosphorylation-resistant pCR3.1-S104, and 107A Snail-Flg in MCF-7 cells specifically induced PTEN down-regulation/inactivation and Akt/PKB activation, without affecting ERK1/2 activity. In addition, Snail prominently suppressed 5-FU-induced increases in p53 levels. These findings demonstrate that Snail switches 5-FU-induced apoptosis to necrosis through the activation of Akt/PKB and the down-regulation of p53 levels.

키워드

참고문헌

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