폐암 세포주 A549에서 FPDHP의 세포사멸 유도 효과 및 기전

Other Titles
Apoptosis-inducing Effects and Mechanisms of FPDHP in Lung Cancer Cell Line, A549
Authors
김선구
Issue Date
2014-06
Awarded Date
2014
Abstract
폐암 세포주인 A549 세포에서 4-(furan-2-yl)-2-(pyridin-2-yl)-5, 6-dihydro-1, 10-phenanthroline(FPDHP)의 세포사멸 유도 효과 및 기전을 규명하고자 하였다. FPDHP는 A549 세포의 증식억제와 세포자멸사 및 대량의 세포탈락을 유발시켰다. FPDHP는 caspase-3 활성화, phospholipase C gamma 1의 분절화를 유발하며, caspase 억제제인 z-VAD 전 처치는 FPDHP에 의해 유도되는 세포자멸사를 차단하였다. FPDHP는 c-FADD-like interleukin-1β-converting enzyme-inhibitory protein(c-FLIP)의 전사를 억제시켰으며, X-linked inhibitor of apoptosis protein(XIAP)의 전사 억제와 단백질 분해를 촉진하였으며, myeloid cell leukemia-1(Mcl-1)의 단백질 분해를 촉진시켰다. FPDHP는 처치농도 및 시간에 비례하여 A549 세포탈락을 유도하였으며, 부착되어 있는 세포에 비해 탈락한 세포에서 세포자멸사를 증가시켰다. 또 인테그린 α1, α5, α6, αv 및 β1의 전사를 감소시켰으며, 인테그린 하부 신호전달에 중요한 역할을 하는 focal adhesion kinase(FAK)의 전사와 인산화를 억제시켰다. PI3K 억제제와 farnesyl transferase 억제제는 FPDHP의 세포사멸 유도 작용에 영향을 미치지 않았으나, N-acetyl-L-cysteine과 calpain 억제제인 PD150606은 부분적으로 FPDHP에 의한 세포사멸을 억제시켰다. PD150606은 또한 FPDHP에 의한 세포탈락과 Mcl-1의 분해를 억제하였다. 이상의 결과는 FPDHP가 caspase-의존적 세포사멸과 calpain-의존적 세포사멸을 유발하는 신규 항암제로서 활용될 가능성이 있음을 나타낸다.
I investigated apoptosis-inducing effects and mechanisms of 4-(furan-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-1, 10-phenanthroline (FPDHP) in A549 cell. FPDHP induced activation of caspase-3 and cleavage of phospholipase C gamma 1 in A549 cells. However, pretreatment of a pan-caspase inhibitor inhibited FPDHP-induced apoptosis in A549 cells. FPDHP reduced mRNA expression in c-FADD-like interleukin-1β-converting enzyme-inhibitory protein and X-linked inhibitor of apoptosis protein (XIAP) while it increased the degradation of myeloid cell leukemia-1 (Mcl-1) and XIAP proteins. The exposure of A549 cells to FPDHP further led to a dose- and time-dependent increase in the number of detached cells from cell culture plate, and there was also an increase in the number of cells in sub-G1 phase in detached cells. In addition, FPDHP decreased mRNA expression in 5 integrins and focal adhesion kinase (FAK). Interestingly, treatment with N-acetyl-L-cysteine or calpain inhibitor (PD150606) partially inhibited FPDHP-mediated apoptosis in A549 cells. PD150606 further blocked FPDHP-induced cell detachment and degradation of Mcl-1 protein in A549 cells. Collectively, these results suggest that FPDHP might be used as a novel anticancer agent that induces both caspase- and calpain-dependent apoptosis in A549 cells.
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/11415
Appears in Collections:
3. Thesis (학위논문) > 1. School of Medicine (의과대학) > 박사
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