3-Hydroxykynurenine (3HK)에 의한 SKN-SH 세포사멸 과정에서 heat shock protein 90에 의한 활성기 산소의 억제 효과
Down-regulated reactive oxygen species by heat shock protein 90 in 3-Hydroxykynurenine-induced SKN-SH cell death
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초록
간질, 염증성 바이러스 감염성 치매 그리고 파킨슨씨병과 같은 몇몇 신경퇴행성 질환에서도 발견되는 3- hydroxykynurenine (3HK)의 신경세포 독성과, 이를 다양한 세포들에서 세포 파괴 상황에서 보호 작용을 하는 것으 로 알려져 있는 열충격 단백질(heat shock protein; HSP)이 보호 작용을 나타낸다고 알려져 있으나, 아직까지 3HK 에 의한 신경세포 사멸에서 활성기 산소 발생의 역할과 이에 대한 HSP 90의 보호 작용 기작은 아직까지 명확히 밝혀지지 않았다. 따라서 본 연구에서는 3HK에 의해 활성기 산소가 축적되고 caspase가 활성화됨으로써 세포 자 멸사가 발생한다는 결과를 제시하였다. 효과적인 항산화 물질로 알려져 있는 N-acetylcysteine (NAC)를 전처리하 였을 때 활성기 산소 축적과 caspase 활성을 억제함으로써 SKN-SH 세포에서 3HK에 의한 세포 자멸사를 효과적 으로 억제하였다. SKN-SH 신경세포에서 3HK에 의한 세포 독성이 열충격 단백질에 의해서 감소되었는데, HSP는 3HK에 의한 활성기 산소 축적과 세포 자멸사를 효과적으로 억제하였다. HSP90 anti-sense oligonucleotide를 전처 리했을 때 HSP의 세포 보호 효과가 사라졌으나, 다른 종류의 HSP anti-sense oligonucleotide를 전처리하였을 경우 에는 세포 보호 효과가 사라지지 않았다. 이러한 결과는 HSP90이 활성기 산소 축적과 caspase 활성화를 감소시킴 으로써 3HK에 의한 세포 독성으로부터 SKN-SH 세포를 보호함을 제시한다.
Abstract
In this present study, we show that 3HK-induced reactive oxygen species (ROS) accumulation and caspase activation lead to apoptotic cell death. Pretreatment with N-acetylcysteine (NAC), an effective antioxidant, significantly attenuated 3HK-induced apoptosis by way of a reduction of ROS accumulation and caspase activity. SKN-SN cells were protected from 3HK-induced cytotoxicity by heat shock protein (HSP). HSP90 effectively attenuated 3HK-mediated ROS accumulation and apoptosis. In addition, the protective effect of HSP90 was abolished by pretreatment with HSP90 antisense oligonucleotide, but not when pretreated with anti-senses for other HSPs. These results suggest that HSP90 protects SKN-SH cells from 3HK-induced cytotoxicity by reducing ROS levels and caspase activity.
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