BMVC衍生物誘發粒線體功能異常對細胞移動能力及其相關調控基因的探討

粒線體是細胞中最主要的能量提供者,同時它也扮演著傳遞訊息以及調控細胞的生長分化和死亡的重要角色。在許多疾病,諸如神經退化性疾病、肌無力、以及癌症中,也發現病患細胞中的粒線體和一般正常的粒線體有所不同,而許多研究也發現這些功能異常的粒線體會造成細胞核內基因表現的改變,此現象稱作「回溯訊息」(retrograde signal)。由本實驗室先前的研究發現,使用 ALA Photodynamic Therapy(ALA-PDT)反覆處理所建立的粒線體功能異常 (mitochondrial dysfunction)細胞株中,癌細胞的移動能力顯著地被抑制,並伴隨著核內基因表現的改變。先前已有研究發現 BMVC-12C 這種小分子化合物可以專一地累積在癌細胞粒線體中,所以本研究想探討 BMVC-12C 能否成為一個使粒線體功能異常的工具,並觀察其後續生物效應是否和本實驗室先前發現的結果相同。首先,在細胞毒性測試的實驗中,我們發現 BMVC-12C 會抑制癌細胞的生長複製, 但在低濃度的情況下並不會造成其死亡。為研究 BMVC-12C 是否會影響粒線體的功能,我們做了一系列對粒線體功能的分析。結果發現伴隨活性氧化物(Reactive Oxygen Species,ROS)的產生,粒線體確實有功能異常的情況,進一步的研究顯示造成粒線體功能異常的原因則是來自於 BMVC-12C 抑制了粒線體 DNA(mtDNA) 的複製。接著,在細胞移動能力的實驗中我們同樣觀察到 BMVC-12C 處理的細胞其移動能力顯著下降。最後,我們將 BMVC-12C 處理過的細胞進行基因表現的分析,發現 PEG-1/MEST 基因的表現量在藥物處理後顯著的下降,呼應先前細胞移動能力的結果,且亦符合之前在 ALA-PDT 中所觀察到的結果。

關鍵字

粒線體功能異常； ALA-PDT ； BMVC-12C ； PEG-1/MEST

並列摘要

Except for providing ATP, mitochondria also regulate cell growth, death, and differentiation. Many studies showed that mitochondrial dysfunction involved in many diseases, like neurodegenerative disease, myopathy, and cancer. It has been shown that mitochondrial dysfunction might affect the expression profile of nuclear genes via the so called “mitochondrial retrograde signaling”. Previously, our lab found that the migration and invasion ability of the PDT-derived variants was significantly decreased. Meanwhile, a small molecule named “BMVC-12C” has been found to localize in mitochondria. In this study, we would like to examine whether BMVC-12C can induce mitochondrial dysfunction and further investigate the following biological consequences. We found out that BMVC-12C can inhibit cell growth at low concentration. Further studies showed that BMVC-12C treatment led to mitochondrial dysfunction and the production of reactive oxygen species (ROS) was also observed. Meanwhile, we found that the BMVC-12C could inhibit the replication of mitochondrial DNA (mtDNA). Finally, we showed that BMVC-12C treatment can reduce cell migration ability and the expression level of PEG-1/MEST gene

並列關鍵字

mitochondrial dysfunction ； ALA-PDT ； BMVC-12C ； PEG-1/MEST

參考文獻

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4. Pieczenik, S.R. and J. Neustadt, Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol, 2007. 83(1): p. 84-92.

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BMVC衍生物誘發粒線體功能異常對細胞移動能力及其相關調控基因的探討

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