Eupafolin Enhances TRAIL-mediated Apoptosis through Cathepsin S-induced Down-regulation of Mcl-1 Expression in Renal Cancer Caki Cells

Other Titles
신장암 세포주에서 Eupafolin과 TRAIL 병합처리에 의한 세포사멸 증진효과
Authors
한민애
Issue Date
2015-12
Awarded Date
2016
Abstract
Eupafolin은 Artemisia princeps Pampanini에서 추출한 플라보노이드의 일종으로 여러 암세포에서 항암효과를 나타낸다고 알려져 있다. 본 연구에서, TRAIL 저항성을 가지는 암세포를 대상으로 eupafolin 이 TRAIL 매개 세포사멸을 증가시킬 수 있는지 여부를 조사하였다. 연구 결과, sub-toxic한 농도의 eupafolin과 TRAIL을 병합하여 처리 하였을 때 신장암 세포주인 Caki 세포에서 caspase 의존적인 세포사멸이 유도되었다. 특히 eupafolin은 Caki 세포에서 lysosomal protease의 일종인 cathepsin S 활성을 통하여 Mcl-1의 발현을 유의적으로 감소시켰으며, Mcl-1이 과발현 되어 있을 경우 Eupafolin과 TRAIL에 의한 세포사멸이 억제되었다. 이를 통해 eupafolin에 의해 증진된 세포사멸에 있어 Mcl-1이 중요한 조절인자임을 확인하였다. 또한 eupafolin은 proteasome 활성을 감소시킴으로써 pro-apoptotic 단백질인 Bim의 발현을 증가시켰으며, siRNA를 사용하여 Bim의 발현을 억제시킬 경우, eupafolin과 TRAIL 매개 세포사멸 또한 억제되었다. 따라서 본 연구의 결과는 eupafolin과 TRAIL의 병합 처리는 TRAIL에 저항성을 가지는 암세포의 사멸을 증진시키는 효과적인 방법임을 의미한다.
Eupafolin, a flavone found in Artemisia princeps Pampanini, has been reported for anti-tumor activity in several cancer cells. In this study, the examined whether eupafolin could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells. This study found that eupafolin alone had no effect on apoptosis, but combined treatment with eupafolin and TRAIL markedly induced apoptosis in Caki cells, as well as glioma cells (U251MG) and prostate cancer cells (DU145). In contrast, combined treatment with eupafolin and TRAIL did not induce apoptosis in normal mesangial cells (MC) and normal mouse kidney cells (TMCK-1). Eupafolin induced down-regulation of Mcl-1 expression at the post-translational levels in lysosome (cathepsin S)-dependent manner, and over-expression of Mcl-1 markedly blocked apoptosis induced by combined treatment with eupafolin and TRAIL. Furthermore, eupafolin increased Bim expression at the post-translational levels via the inhibition of proteasome activity. Moreover, knock-down of Bim expression by siRNA partially inhibited eupafolin plus TRAIL-induced apoptosis. Furthermore, combined treatment with eupafolin and TRAIL reduced tumor growth compared with either drug alone in xenograft models. Taken together, these results suggest that eupafolin enhanced TRAIL-mediated apoptosis via down-regulation of Mcl-1 and up-regulation of Bim in renal carcinoma Caki cells.
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/11306
Appears in Collections:
3. Thesis (학위논문) > 1. School of Medicine (의과대학) > 석사
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http://dcollection.kmu.ac.kr/jsp/common/DcLoOrgPer.jsp?sItemId=000000051905
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