探討Irisin對人類神經膠質瘤細胞的訊號傳遞機制

Abstract

運動被認為是可以預防許多的疾病，例如心血管疾病以及癌症，其中因運動而分泌的運動激素被認為扮演著重要的角色。Irisin 是一種在運動時被分泌的運動激素能透過棕化白色脂肪細胞成類棕色脂肪細胞而增加能量的消耗。許多文章也報導irisin能抑制許多種癌細胞的細胞增生。在本篇論文中我們純化帶有GST-tag的irisin重組蛋白並用來抑制神經膠質瘤細胞U-87 MG 的細胞增生， irisin能誘導p21的表現以及抑制cdc2磷酸化，而導致細胞於細胞週期G2/M期的數量上升。為了進一步探討irisin是透過何種訊息傳遞機制來抑制U-87 MG的細胞增生，於此論文中，利用針對訊息傳遞路徑多種專一性抗體及搭配抑制劑以西方墨點法分析。結果中發現irisin能結合在U-87 MG的細胞表面並結合到整合素αV受體。Irisin能經由整合素αV調節下游的訊息傳遞鏈，包括FAK和 JNK，然而AKT路徑可能是被其他受體所啟動。Irisin能誘導整合素αV下游的FAK/JNK路徑以及被其他受體啟動的AKT路徑提升Modaw20的表現，可能進而促進p21蛋白的表現以及氧化調節式的細胞死亡。儘管目前研究對irisin在癌細胞中作用的分子機制並不是完全了解，但irisin是極具有潛力治療癌症的藥物。

Several studies demonstrate that exercise is able to reduce disease incidence, such as cardiovascular diseases and cancer. The exercise-induced myokine is considered to play key mediator on cancer inhibition. Irisin is a myokine which is secreted by muscle cells during exercise, stimulating white adipose browning, to brown-like adipocytes, resulting in reducing the risk of obesity. Many studies find that irisin can inhibit the proliferation of several types of cancer cells. To investigate the irisin effects on cancer cells, the GST-tag human recombinant irisin was purified and utilized to inhibit cell proliferation of glioblastoma cell line, U-87 MG. Moreover, irisin-induced p21 upregulation and the inhibition of cdc2 might cause cell cycle G2/M phase arrest. To decipher the molecular mechanism that irisin reduced cell proliferation of U-87 MG cells, the irisin-induced signal transduction pathways was studied in this thesis. Our result showed that irisin bound to the live U-87 MG cells surface and specifically bind to the integrin αV receptors. The integrin αV receptor downstream signal transduction pathways, including FAK and JNK were regulated by irisin, but AKT pathway was activated by other receptors. Both the integrin αV activated FAK/JNK pathway and other receptors activated AKT pathway was able to upregulated the Modaw20 expression which might induce p21 expression and oxidative regulated cell death. Although the molecular mechanism of irisin effect on cancer cells is not completely clear yet, irisin is a potential therapeutic candidate for cancer therapy.