Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Induction of Apoptosis and Antitumor Activity by Stichoposide D through the Generation of Ceramide in Human Leukemia Cells

Stichoposide D의 백혈병 세포주에서 세라마이드 생성을 통한 세포 사멸 유도 및 항암 작용

  • Park, Eun-Seon (Department of Boichemistry, Dong-A University College of Medicine) ;
  • Yun, Seung-Hoon (Department of Boichemistry, Dong-A University College of Medicine) ;
  • Shin, Sung-Won (Department of Boichemistry, Dong-A University College of Medicine) ;
  • Kwak, Jong-Young (Department of Boichemistry, Dong-A University College of Medicine) ;
  • Park, Joo-In (Department of Boichemistry, Dong-A University College of Medicine)
  • 박은선 (동아대학교 의과대학 생화학교실) ;
  • 윤성훈 (동아대학교 의과대학 생화학교실) ;
  • 신성원 (동아대학교 의과대학 생화학교실) ;
  • 곽종영 (동아대학교 의과대학 생화학교실) ;
  • 박주인 (동아대학교 의과대학 생화학교실)
  • Received : 2012.03.06
  • Accepted : 2012.06.17
  • Published : 2012.06.30
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Abstract

Marine triterpene glycosides are physiologically active natural compounds isolated from sea cucumbers(holothurians). It was demonstrated that they have a wide range of biological activities, including antifungal, cytotoxic, and antitumor effects. A previous study showed that stichoposide C (STC) isolated from Thelenota anax induces apoptosis through generation of ceramide by activation of acid sphingomyelinase (SMase) and neutral SMase in human leukemia cells. In this study, we investigated whether STD, a structural analog of STC, can induce apoptosis and examined the molecular mechanisms for its activity. It was found that STC and STD induce apoptosis in a dose- and time-dependent manner and lead to the activation of caspase-8, mitochondrial damage, activation of caspase-9, and activation of caspase-3 in K562 and HL-60 cells. STC activates acid SMase and neutral SMase, which results in the generation of ceramide. Specific inhibition of acid SMase or neutral SMase partially blocked STC-induced apoptosis, but not STD-induced apoptosis. In contrast, STD generates ceramide through the activation of ceramide synthase. Specific inhibition of ceramide synthase partially blocked STD-induced apoptosis, but not STC-induced apoptosis. Moreover, STC and STD markedly reduced tumor growth of HL-60 xenograft tumors and increased ceramide generation in vivo. These results indicate that STC and STD can induce apoptosis and have antitumor activity through the different molecular mechanisms, because they have a different sugar residue attached to aglycones. Thus, these results suggest that their actions are affected by a sugar residue attached to aglycones and they can be used as anticancer agents in the treatment of leukemia.

해양 트리테르펜 글리코시드(marine triterpene glycosides)는 해삼(Holothurians)으로부터 분리된 천연물질로서 항 진균작용, 항암작용 및 용혈 작용 등 여러 가지 생물학적 활성들을 가지고 있다고 보고되었다. 또한 이전의 연구 결과 Thelenota anax로부터 분리한 stichoposide C (STC)는 산성 스핑고마이엘리나제와 중성 스핑고마이엘리나제의 활성화에 의한 세라마이드의 생성을 통하여 백혈병 세포주에서 세포사멸을 유도한다는 것을 알 수 있었다. 본 연구에서는 STC와 구조 유사체인 STD가 백혈병 세포에서 세포사멸을 유도하는지와 이에 대한 분자적 기전을 살펴보았다. STC와 STD는 K562 세포와 HL-60 세포에서 농도와 시간 의존적으로 세포 사멸을 일으키고 이러한 세포 사멸은 caspase-8의 활성화, 미토콘드리아 손상, caspase-9의 활성화, 그리고 caspase-3의 활성화에 의해 유도된다. 이러한 결과는 STC와 STD가 외인성 경로와 내인성 경로의 활성화를 통해 세포 사멸을 유도함을 시사한다. 그리고 STC는 산성 SMase와 중성 SMase를 활성화시키고 이 결과로 세라마이드를 생성시킨다. 산성과 중성 SMase의 특이적인 저해제를 이용하여 STC에 의한 세포 사멸이 부분적으로 억제됨을 알 수 있었다. 반면에, STD는 세라마이드 합성 효소의 활성화에 의해서 세라마이드를 생성시킨다. 세라마이드 합성 효소 저해제를 이용하여 STD에 의한 세포 사멸이 부분적으로 억제되는 것을 확인하였다. 더욱이 STC와 STD는 HL-60 세포의 이종 이식 종양 모델에서 종양의 성장을 현저하게 억제하였고 세라마이드의 생성도 증가시켰다. 이러한 결과는 STC와 STD가 aglycone에 부착된 당이 다르므로 서로 다른 경로를 통해 세포 사멸과 항암 활성을 유도한다는 것을 암시하였다. 따라서 이러한 결과는 이들의 작용은 aglycone에 부착된 당에 의해 영향을 받을 수 있고 이들은 향후 백혈병의 치료제로 사용될 수 있다는 것을 제시하였다.

Keywords

References

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