Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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YM155 Induces Apoptosis through Downregulation of Anti-apoptotic Proteins in Head and Neck AMC-HN4 Cells

YM155 처리에 의한 두경부 암 AMC-HN4 세포 세포자멸사 유도 효과

  • Chang, Ho Joon (Department of Otolaryngology, School of Medicine, Keimyung University) ;
  • Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University) ;
  • Kim, Dong Eun (Department of Otolaryngology, School of Medicine, Keimyung University)
  • 장호준 (계명대학교 의과대학 이비인후과) ;
  • 권택규 (계명대학교 의과대학 면역학교실) ;
  • 김동은 (계명대학교 의과대학 이비인후과)
  • Received : 2019.02.07
  • Accepted : 2019.02.12
  • Published : 2019.03.30
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Abstract

Squamous cell carcinoma is the primary tumor type in head and neck cancers, the fifth most common malignant neoplasm world-wide. Survivin, a member of the inhibitor of apoptosis family, is highly expressed in head and neck carcinoma patients and correlated with more aggressive forms. In this study, we investigated whether YM155, a specific survivin inhibitor, could induce apoptosis in head and neck AMC-HN4 cells. YM155 was found to markedly induce apoptosis and cleavage of PARP, a marker of apoptosis. Furthermore, YM155 promoted apoptosis in other cancer cells, such as glioma (U251MG) and renal carcinoma (Caki) cells. In contrast, YM155 had no effect on apoptosis in normal mesangial cells. YM155 significantly induced caspase activation, and pan caspase inhibitor z-VAD-fmk markedly blocked apoptosis, PARP cleavage, and caspase-3 cleavage. Therefore, YM155 was seen to instigate caspase-dependent apoptosis in head and neck AMC-HN4 cells, inducing downregulation of survivin as well as other apoptotic proteins such as c-FLIP and Mcl-1. In addition, the induction of apoptosis and PARP cleavage by YM155 treatment was effectively inhibited in survivin-, c-FLIP- and Mcl-1-over-expressing head and neck AMC-HN4 cells. In conclusion, YM155 is a potent candidate for inducing cell death in head and neck AMC-HN4 cells.

두경부암은 전세계에서 발병률이 여섯 번째로 높은 암으로 그동안 수술적 치료를 선호하였으나 광범위한 절제에 따른 기능적 장애로 인해 항암치료에 대한 관심이 높아지고 있다. 두경부암에서 cisplatin이 가장 많이 사용되는 항암제이나 cisplatin 내성이 문제가 되고 있다. 따라서 부작용은 줄이고, 약제내성 기전에 대해 이해하여 암세포의 사멸은 증대시키는 새로운 항암제의 개발이 필요하다. Survivin은 inhibitor of apoptosis proteins (IAPs) family 중 하나로 두경부암에서 과발현되어 있다. YM155는 survivin을 억제하는 분자로 본 연구를 통해 YM155의 처리 후 두경부 암세포의 세포자멸사가 유도되며, 뇌암 세포와 신장암 세포에서도 세포자멸사가 유도됨을 확인할 수 있었다. 반면에 정상세포인 mesangial cells에는 YM155가 세포자멸사에 영향을 주지 않았다. YM155는 caspase의 활성화를 통해 세포자멸사를 촉진하며, anti-apoptotic protein인 c-FLIP, Mcl-1, survivin의 발현을 저해하는 것으로 확인되었다. YM155는 두경부 뿐만 아니라 다른 장기의 악성종양 치료법의 개발에 활용 될 수 있을 것으로 생각된다.

Keywords

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Fig. 1. AMC-HN4 cells were treated with different doses of YM155.

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Fig. 2. YM155-induced apoptosis is dependent on caspase activation in AMC-HN4 cells.

SMGHBM_2019_v29n3_318_f0003.png 이미지

Fig. 3. The effects of treatment with YM155 on expression of apoptosis related proteins.

SMGHBM_2019_v29n3_318_f0004.png 이미지

Fig. 4. Down-regulation of c-FLIP, Mcl-1 and survivin contributes to YM155-mediated apoptosis.

SMGHBM_2019_v29n3_318_f0005.png 이미지

Fig. 5. The effects of YM155 on apoptosis in other carcinoma cell lines and normal cells.

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