本文關(guān)鍵詞：硫利達(dá)嗪通過內(nèi)質(zhì)網(wǎng)應(yīng)激介導(dǎo)DR5表達(dá)上調(diào)增敏TRAIL對(duì)肺癌PC9細(xì)胞的促凋亡效應(yīng)　出處：《中國(guó)肺癌雜志》2017年02期 　論文類型：期刊論文

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【摘要】：背景與目的腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(tumor necrosis factor-related apoptosis-inducting ligand,TRAIL)可誘導(dǎo)腫瘤細(xì)胞發(fā)生凋亡,然而相當(dāng)數(shù)量的腫瘤細(xì)胞可耐受TRAIL誘導(dǎo)的凋亡而得以存活。本實(shí)驗(yàn)觀察硫利達(dá)嗪(thioridazine,THZ)通過誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激(endoplasmic reticulum stress,ER stress)介導(dǎo)的死亡受體5(death receptor 5,DR5)表達(dá)上調(diào),繼而增敏TRAIL對(duì)肺腺癌細(xì)胞PC9的生長(zhǎng)抑制及凋亡誘導(dǎo)效應(yīng),探討其機(jī)制。方法不同濃度硫利達(dá)嗪及TRAIL單獨(dú)或聯(lián)合處理PC9細(xì)胞,MTT法檢測(cè)細(xì)胞活性變化,流式細(xì)胞術(shù)檢測(cè)細(xì)胞表面DR5表達(dá)及細(xì)胞凋亡率,Western blotting檢測(cè)內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)蛋白GRP78(glucose regulated protein 78)、C/EBP環(huán)磷酸腺苷反應(yīng)元件結(jié)合轉(zhuǎn)錄因子同源蛋白(C/EBP homologous protein,CHOP)、p-PERK(PKR-like ER kinase)、p-e IF2α(eukaryotic initiation factor-2α,e IF2α)、ATF4(activating transcription factor 4,ATF4)及凋亡相關(guān)蛋白Caspase-3、Caspase-9、Caspase-8、PARP、DR5表達(dá)變化。結(jié)果硫利達(dá)嗪對(duì)PC9細(xì)胞的增殖抑制效應(yīng)呈濃度依賴性(P0.05),硫利達(dá)嗪可增加TRAIL對(duì)PC9細(xì)胞的抑制作用及凋亡誘導(dǎo)作用且可上調(diào)PC9細(xì)胞表面DR5表達(dá)水平,流式細(xì)胞術(shù)結(jié)果顯示:TRAIL聯(lián)合硫利達(dá)嗪組細(xì)胞凋亡率較單獨(dú)TRAIL組顯著增加(P0.05),Western blotting結(jié)果顯示:TRAIL聯(lián)合硫利達(dá)嗪組細(xì)胞Cleaved-caspase-8、Cleaved-PARP、DR5表達(dá)水平較單獨(dú)TRAIL組明顯上調(diào)。DR5表達(dá)上調(diào)及促凋亡效應(yīng)是通過誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激發(fā)生,并伴隨著GRP78及CHOP表達(dá)上調(diào)發(fā)生的,且該效應(yīng)可被4-苯基丁酸(4-phenylbutyric acid,4-PBA)可抑制(P0.05)。結(jié)論硫利達(dá)嗪增敏TRAIL對(duì)PC9細(xì)胞的增殖抑制效應(yīng)顯著,其機(jī)制可能與硫利達(dá)嗪內(nèi)質(zhì)網(wǎng)應(yīng)激介導(dǎo)的DR5上調(diào)有關(guān)。
[Abstract]:Background and objective tumor necrosis factor-related apoptosis-inducing ligands. Tumor necrosis factor-related apoptosis-inducting ligand. Trail can induce apoptosis of tumor cells. However, a considerable number of tumor cells could survive the apoptosis induced by TRAIL. THZ induced endoplasmic reticulum stress by endoplasmic reticulum stress. The expression of ER stress-mediated death receptor 5 death receptor 5 DR5 was up-regulated. Then the growth inhibition and apoptosis induction of lung adenocarcinoma cell line PC9 were investigated by sensitizing TRAIL. Methods PC9 cells were treated with different concentrations of talidazide and TRAIL alone or in combination. MTT assay was used to detect the changes of cell activity, and flow cytometry was used to detect the expression of DR5 and the rate of apoptosis. The endoplasmic reticulum stress-related protein (GRP78(glucose regulated protein 78) was detected by Western blotting. C / EBP homologous protein (CHOP5), a transcription factor homologous protein, is bound by the C / EBP cyclic adenosine monophosphate response element. P-PERKU PKR-like ER kinase factor-2 偽 -e IF2 偽 eukaryotic initiation factor-2 偽. E IF2 偽 ATF4activation transcription factor 4 ATF4) and apoptosis-related protein Caspase-3. Results the inhibitory effect of thiridamine on the proliferation of PC9 cells was in a concentration dependent manner (P 0.05). Tiridazide could increase the inhibitory effect and apoptosis induction of TRAIL on PC9 cells and up-regulate the expression of DR5 on the surface of PC9 cells. The results of flow cytometry showed that the apoptosis rate of TRAIL group was significantly higher than that of TRAIL group (P 0.05). The results of Western blotting showed that the cell line Cleaved-caspase-8 was Cleaved-PARP. Compared with TRAIL group, the expression of DR5 increased significantly. DR5 expression and apoptosis were induced by endoplasmic reticulum stress, accompanied by the up-regulation of GRP78 and CHOP expression. The effect can be obtained by 4-phenylbutyric acid. Conclusion tiridamine sensitized TRAIL can inhibit the proliferation of PC9 cells. The mechanism may be related to the upregulation of DR5 mediated by endoplasmic reticulum stress.
【作者單位】： 安徽醫(yī)科大學(xué)第三附屬醫(yī)院(合肥市第一人民醫(yī)院)腫瘤科;合肥市濱湖醫(yī)院中心實(shí)驗(yàn)室;
【基金】：國(guó)家重點(diǎn)外國(guó)專家項(xiàng)目(No.20163400008) 安徽省重點(diǎn)外國(guó)專家項(xiàng)目(No.20153400062)資助~~
【分類號(hào)】：R734.2
【正文快照】： 腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體(tumor necrosis factor-related apoptosis-inducting ligand,TRAIL)屬于TNF超家族,可誘導(dǎo)腫瘤細(xì)胞發(fā)生凋亡。TRAIL可通過與其受體TRAIL-R1(death receptor 4,DR4)、TRAIL-R2(death receptor 5,DR5)結(jié)合促使靶細(xì)胞發(fā)生凋亡。然而,相當(dāng)數(shù)量的腫瘤

【參考文獻(xiàn)】

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1 余玉;陳U，

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