吡唑環(huán)氧烷衍生物3g對結(jié)腸癌細(xì)胞自噬和細(xì)胞周期的調(diào)節(jié)及分子機(jī)制研究
發(fā)布時(shí)間：2018-08-02 21:43
【摘要】：研究背景和研究目的結(jié)腸癌在在人類常見的癌癥中的被診斷率已經(jīng)躍居第三位。在癌癥的治療中,除了局部切除治療外,化療仍然是一個(gè)普遍并有效的方式。許多聯(lián)合給藥的治療方案中,化療藥物都具有一定的毒副作用。篩選新型小分子化合物抑制腫瘤細(xì)胞生長并且研究其具體機(jī)制仍然是研究中的熱點(diǎn)。并且通過化學(xué)遺傳學(xué)的方法研究細(xì)胞程序性死亡和細(xì)胞周期的具體機(jī)制能夠?yàn)榇龠M(jìn)藥物開發(fā),為腫瘤治療打下理論基礎(chǔ)。細(xì)胞程序性死亡可以被分為三大類,凋亡是其中的一個(gè)重要類型,在多細(xì)胞生物的正常發(fā)育和穩(wěn)態(tài)保持中有著關(guān)鍵的調(diào)控作用。凋亡是去除不需要的、衰老的和受損的細(xì)胞的重要機(jī)制,凋亡的失調(diào)會(huì)導(dǎo)致多種疾病,其中包括癌癥的發(fā)展。自噬是另一類重要的細(xì)胞程序性死亡,在正常條件下可以通過降解多余的細(xì)胞器和細(xì)胞內(nèi)錯(cuò)誤折疊的蛋白等,來提供營養(yǎng)用以維持細(xì)胞正常的生命活動(dòng)。但是在凋亡缺陷性細(xì)胞的死亡中,自噬又是細(xì)胞死亡必需的,這表明了自噬的雙重性。自噬的調(diào)節(jié)是一個(gè)精密而復(fù)雜的基因調(diào)控過程,在各階段都受到多種調(diào)節(jié)因子的作用。自噬可以分為mTOR依賴途徑和mTOR非依賴途徑,在前者中主要的分子機(jī)制是通過Akt/mTOR信號(hào)通路和其下游底物發(fā)揮作用,并參與調(diào)節(jié)翻譯和細(xì)胞生長。而細(xì)胞自噬和周期也相互聯(lián)系,并且mTOR在其中發(fā)揮重要作用。在我們實(shí)驗(yàn)室的前期工作中,發(fā)現(xiàn)在除血清和生長因子條件誘導(dǎo)的血管內(nèi)皮細(xì)胞的凋亡過程中,小分子化合物3g通過誘導(dǎo)Ingerinβ4蛋白磷酸化并誘導(dǎo)入核,從而有效地誘導(dǎo)血管內(nèi)皮細(xì)胞凋亡。但是其是否能夠在腫瘤細(xì)胞中發(fā)揮抑制生長的作用從而成為一個(gè)有效的腫瘤治療藥物則還不清楚。而且其是否會(huì)對正常細(xì)胞的生長產(chǎn)生影響是尋找新型藥物的重點(diǎn)之一,尋找到能夠特異性抑制腫瘤細(xì)胞的化合物能夠?yàn)樗幬镩_發(fā)提供新的前景。磷脂酰乙醇胺結(jié)合蛋白1(PEBP1),也被稱為Raf激酶抑制蛋白,參與了MAPK,GPCR,NF-κB,GSK3β等多種細(xì)胞生長相關(guān)的信號(hào)通路的調(diào)控。PEBP1可以通過參與多種將細(xì)胞外刺激轉(zhuǎn)化成不同信號(hào)以維持細(xì)胞完整性和體內(nèi)平衡的通路。結(jié)腸癌患者的PEBP1啟動(dòng)子甲基化程度遠(yuǎn)遠(yuǎn)高于正常樣本,這表明了其異常在結(jié)腸癌起始中潛在的重要性。而且最新的研究中PEBP1和LC3的直接相互作用得到了驗(yàn)證,PEBP1通過保守的LIR基序和LC3結(jié)合并且抑制營養(yǎng)剝奪的自噬,而且是通過PEBP1S153的磷酸化發(fā)揮作用的。本研究利用化學(xué)遺傳學(xué)的原理與技術(shù),以化合物小分子3g為研究工具,研究了其特異性抑制結(jié)腸癌細(xì)胞生長中的具體分子機(jī)制,確定了其在調(diào)控細(xì)胞自噬和細(xì)胞周期中發(fā)揮的作用,為結(jié)腸癌的治療提供新的靶點(diǎn)和有效工具。研究方法1.人結(jié)腸癌Hct116細(xì)胞、人臍靜脈血管內(nèi)皮細(xì)胞、人肺腺癌A549細(xì)胞、人宮頸癌HeLa細(xì)胞、人前列腺癌PC3細(xì)胞的培養(yǎng)2.倒置相差顯微鏡觀察細(xì)胞形態(tài)學(xué)變化3.SRB法檢測細(xì)胞存活率4.Heochest染色后,通過熒光顯微鏡觀察細(xì)胞核形態(tài)的變化,從而判斷細(xì)胞是否凋亡5.LDH(乳酸脫氫酶)檢測細(xì)胞是否發(fā)生壞死6.流式細(xì)胞術(shù)檢測細(xì)胞凋亡和細(xì)胞周期7.激光共聚焦顯微鏡檢測LC3-II的分布8.western blot檢測PARP和caspase-3蛋白切割水平,LC3-II和p62蛋白表達(dá)水平,以及Akt,mTOR,P70S6K,4EBP1,PEBP1的磷酸化水平9.雞胚尿囊膜人移植瘤模型研究小分子化合物對實(shí)體瘤進(jìn)展和正常血管生成的影響研究結(jié)果1.吡唑環(huán)氧烷衍生物具有對多種腫瘤細(xì)胞的生長抑制作用1.1 SRB檢測結(jié)果表明,小分子化合物3g(1-10 μM)作用于多種腫瘤細(xì)胞后,均能顯著抑制細(xì)胞的存活。其中,化合物對結(jié)腸癌細(xì)胞Hct116細(xì)胞的抑制作用最強(qiáng)。并且在同樣濃度下不影響正常培養(yǎng)條件的血管內(nèi)皮細(xì)胞生長。1.2倒置相差顯微鏡觀察細(xì)胞形態(tài)發(fā)現(xiàn),化合物3g(2.5-10 μM)處理Hct1 16細(xì)胞24h后,細(xì)胞逐漸變圓。而3g處理A549細(xì)胞24h后,細(xì)胞發(fā)生了明顯的拉長。1.3 Heochest染色結(jié)合熒光顯微鏡觀察化合物3g(2.5-10 μM)處理腫瘤細(xì)胞24 h后,核凝集現(xiàn)象與對照組相比變化不明顯。1.4流式細(xì)胞術(shù)結(jié)果表明,化合物3g(5μM)處理Hct116細(xì)胞24h后,處理組與對照組相比凋亡率沒有發(fā)現(xiàn)顯著升高1.5 Western-blot 檢測在 12h、24h、48h 時(shí) 3g(5 μM)可能不能誘導(dǎo) PARP 和caspase-3切割上調(diào)。1.6 LDH檢測發(fā)現(xiàn),化合物3g(10 μM)處理多種腫瘤細(xì)胞48 h后,培養(yǎng)液上清中LDH活性沒有顯著性差異,表明細(xì)胞沒有發(fā)生壞死。2.小分子化合物3g通過調(diào)節(jié)細(xì)胞自噬和細(xì)胞周期發(fā)揮抑制作用2.1通過流式細(xì)胞術(shù)發(fā)現(xiàn)3g(5μM)處理Hct116細(xì)胞24h后會(huì)引起G1期細(xì)胞阻滯。2.2 western blot結(jié)果表明,設(shè)計(jì)不同的時(shí)間點(diǎn)使用3g(5 μM)處理Hct1 16細(xì)胞后,與對照組相比,3h、6h時(shí)Hct116細(xì)胞中LC3-Ⅱ表達(dá)顯著增強(qiáng),而在48h時(shí)自噬流被明顯阻斷。2.3免疫細(xì)胞化學(xué)檢測發(fā)現(xiàn),3g(5 μM)處理Hct116細(xì)胞3h后,與對照組相比,Hct116細(xì)胞中LC3出現(xiàn)了點(diǎn)狀聚集。2.4 western blot結(jié)果表明,使用3g(5μM)處理Hct116細(xì)胞后,與對照組相比,短時(shí)間內(nèi)Hct1 16細(xì)胞中Akt和mTOR的磷酸化被抑制。2.5 western blot結(jié)果表明,使用3g(5 μM)處理Hct1 16細(xì)胞后,與對照組相比,短時(shí)間內(nèi)Hct116細(xì)胞中mTOR的底物P70S6K和4EBP1的磷酸化被抑制。2.6 Western blot結(jié)果表明,使用3g(5 μM)處理H116細(xì)胞后,與對照組相比,短時(shí)間內(nèi)Hct1 16細(xì)胞中PEBP1的磷酸化被抑制。2.7雞胚尿囊膜人移植瘤模型在3g處理后,對比對照組,處理組的實(shí)體瘤發(fā)展被明顯抑制,并且不影響其正常血管的發(fā)生。結(jié)論1.小分子化合物3g能夠顯著抑制多種人腫瘤細(xì)胞存活,且抑制作用呈現(xiàn)濃度的依賴性,其中對Hct116細(xì)胞的抑制作用最強(qiáng),并且在同樣濃度下不影響正常培養(yǎng)液培養(yǎng)的人臍靜脈血管內(nèi)皮細(xì)胞。2.小分子化合物3g不是通過誘導(dǎo)凋亡來抑制Hct1 16細(xì)胞的生長。小分子化合物3g能夠在短時(shí)期內(nèi)誘導(dǎo)自噬,而在長時(shí)間時(shí)阻斷自噬流,并且發(fā)揮誘導(dǎo)細(xì)胞周期阻滯的作用。其具體分子機(jī)制是通過在短期內(nèi)誘導(dǎo)PEBP1 S153位點(diǎn)的磷酸化,并抑制Akt/mTOR信號(hào)通路實(shí)現(xiàn)的。PEBP1的磷酸化可能能夠參與調(diào)解mTOR依賴的細(xì)胞自噬。3.小分子化合物3g能夠在雞胚尿囊膜人移植瘤模型中抑制實(shí)體瘤的發(fā)展,說明其有發(fā)展成為腫瘤抑制藥物的前景。
[Abstract]:Background and research objectives of colon cancer are third in the diagnosis of human cancer. In the treatment of cancer, chemotherapy is still a common and effective way in addition to local resection. Subcompounds inhibit the growth of tumor cells and study their specific mechanism is still a hot spot in the study. And the specific mechanism of cell programmed cell death and cell cycle can be studied by chemical genetics to promote drug development and to lay a theoretical foundation for cancer treatment. Cell programmed death can be divided into three major categories, apoptosis It is one of the important types in which there is a key regulatory role in the normal development and homeostasis of multicellular organisms. Apoptosis is an important mechanism for removing the non needed, aging and damaged cells. The dysregulation of apoptosis can lead to a variety of diseases, including the development of cancer. Autophagy is another important type of cell programmed death. Normal conditions can be used to provide nutritional use to maintain normal cell life activities by degrading superfluous organelles and incorrectly folding proteins in cells. However, autophagy is essential for cell death in the death of apoptotic cells, which indicates the dual nature of autophagy. Autophagy is a precise and complex gene. The regulation process is affected by a variety of regulatory factors at all stages. Autophagy can be divided into mTOR dependent and mTOR non dependent pathways. In the former, the main molecular mechanism is to play the role of the Akt/mTOR signaling pathway and its downstream substrate, and to regulate translation and cell growth. In our previous work, we found that during the apoptosis of vascular endothelial cells induced by sera and growth factors, the small molecule compound 3G could induce Ingerin beta 4 protein phosphorylation and inducement, which could effectively induce the apoptosis of vascular endothelial cells. It is not clear that cells can play a role in inhibiting growth and become an effective tumor therapy drug. And whether it will affect the growth of normal cells is one of the key points for finding new drugs, and finding compounds that can specifically inhibit tumor cells can provide new prospects for drug development. Amine binding protein 1 (PEBP1), also known as Raf kinase suppressor, participates in the regulation of a variety of cell growth related signaling pathways such as MAPK, GPCR, NF- kappa B, GSK3 beta and other signaling pathways..PEBP1 can be involved in a variety of pathways that convert extracellular stimuli into different signals to maintain cell integrity and body balance. PEBP1 start Zi Jiaji in colon cancer patients This shows the potential importance of the abnormalities in the initiation of colon cancer. And in the latest studies, the direct interaction between PEBP1 and LC3 is verified, and PEBP1 combines the conservative LIR motif with LC3 and inhibits the autophagy of nutritional deprivation, and is mediated by the phosphorylation of PEBP1S153. The principles and techniques of chemical genetics are used to study the specific molecular mechanism of the small molecule 3G, which inhibits the growth of colon cancer cells, and determine its role in the regulation of autophagy and cell cycle, and provide new targets and effective tools for the treatment of colon cancer. 1. research methods have been made. Colon cancer Hct116 cells, human umbilical vein endothelial cells, human lung adenocarcinoma A549 cells, human cervical cancer HeLa cells, human prostate cancer PC3 cells, 2. inverted phase contrast microscope observation cell morphological changes, 3.SRB method to detect cell survival rate 4.Heochest staining, by fluorescence microscopy to observe the change of cell nuclear morphology, so as to judge the fine. Whether cell apoptosis 5.LDH (lactate dehydrogenase) detected cell necrosis and 6. flow cytometry to detect cell apoptosis and cell cycle 7. laser confocal microscopy detection of LC3-II distribution by 8.western blot detection of PARP and caspase-3 protein cutting levels, LC3-II and p62 protein expression levels, and Akt, mTOR, P70S6K, 4EBP1, phosphorylated water Study on the effect of small molecular compound on the progression of solid tumor and the formation of normal angiogenesis in the human fetal allantoic membrane model of 9. chick embryo. 1. the inhibitory effect of pyrazoloxane derivatives on the growth of various tumor cells was 1.1 SRB. The results showed that the small molecule compound 3G (1-10 mu M) could be significantly inhibited after a variety of tumor cells. The inhibitory effect of the compound on the colon cancer cell Hct116 cells was the strongest, and the cell morphology of the vascular endothelial cells, which did not affect the normal culture conditions under the same concentration, was observed by the.1.2 inversion phase contrast microscope, and the compound 3G (2.5-10 mu M) treated Hct1 16 cells 24h, and the cells gradually turned round. 3G treated A549. After the cell 24h, the cells had an obvious elongated.1.3 Heochest staining combined with the fluorescence microscope to observe the compound 3G (2.5-10 micron M) treatment of the tumor cell 24 h, and the nuclear agglutination was not obvious compared with the control group. The result of.1.4 flow cytometry showed that the compound 3G (5 micron M) treated Hct116 cell 24h, compared with the control group, the rate of apoptosis was no more than that of the control group. There was a significant increase of 1.5 Western-blot detection at 12h, 24h, and 48h 3G (5 M) may not induce PARP and caspase-3 cutting up up.1.6 LDH detection, compound 3G (10 micron) treatment of a variety of tumor cells 48, there is no significant difference in the activity of the culture liquid supernatant. Overregulation of autophagy and cell cycle inhibits the cell cycle 2.1 through flow cytometry that 3G (5 M) treatment of Hct116 cells 24h will cause G1 phase cell block.2.2 Western blot results, and the design of different time points using 3G (5 micron M) treatment Hct1 16 cells, compared with the control group, the expression significantly increased At the time of 48h, autophagic flow was obviously blocked by.2.3 immunocytochemical detection, and 3G (5 mu M) treated Hct116 cells 3H. Compared with the control group, LC3 appeared in Hct116 cells, and.2.4 Western blot results showed that after treating the cells with 3G (5 mu), compared with the control group, the 16 cells in a short period of time were phosphoric acid and phosphoric acid. The inhibition of.2.5 Western blot results showed that after Hct1 16 cells were treated with 3G (5 mu M), the phosphorylation of mTOR substrate P70S6K and 4EBP1 in Hct116 cells in a short time compared with the control group was suppressed.2.6 Western results showed that the phosphorous of 16 cells in a short time compared with the control group was compared with the control group. .2.7 chick embryo allantoic membrane human transplanted tumor model was suppressed after 3G treatment, compared with the control group, the development of solid tumor in the treatment group was obviously inhibited, and it did not affect the occurrence of normal blood vessels. Conclusion 1. small molecule compound 3G can significantly inhibit the survival of various human tumor cells, and the inhibitory production concentration dependence, among them, Hct116 thin The inhibitory effect of the cell is the strongest, and the.2. small molecule compound, 3G, which does not affect the normal culture medium, does not inhibit the growth of Hct1 16 cells by inducing apoptosis. The small molecule compound 3G can induce autophagy in a short period of time, and the autophagy is blocked at a long time, and the induction of autophagy can be induced. The role of cell cycle arrest. Its specific molecular mechanism is the phosphorylation of the PEBP1 S153 site in the short term, and the phosphorylation of the.PEBP1, realized by the Akt/mTOR signaling pathway, may be able to participate in the mediation of the mTOR dependent cell autophagic.3. small molecule compound 3G to inhibit the growth of solid tumor in the human embryo transfer tumor model of the chicken embryo. It shows that it has the prospect of developing tumor suppressor drugs.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.35
[Abstract]:Background and research objectives of colon cancer are third in the diagnosis of human cancer. In the treatment of cancer, chemotherapy is still a common and effective way in addition to local resection. Subcompounds inhibit the growth of tumor cells and study their specific mechanism is still a hot spot in the study. And the specific mechanism of cell programmed cell death and cell cycle can be studied by chemical genetics to promote drug development and to lay a theoretical foundation for cancer treatment. Cell programmed death can be divided into three major categories, apoptosis It is one of the important types in which there is a key regulatory role in the normal development and homeostasis of multicellular organisms. Apoptosis is an important mechanism for removing the non needed, aging and damaged cells. The dysregulation of apoptosis can lead to a variety of diseases, including the development of cancer. Autophagy is another important type of cell programmed death. Normal conditions can be used to provide nutritional use to maintain normal cell life activities by degrading superfluous organelles and incorrectly folding proteins in cells. However, autophagy is essential for cell death in the death of apoptotic cells, which indicates the dual nature of autophagy. Autophagy is a precise and complex gene. The regulation process is affected by a variety of regulatory factors at all stages. Autophagy can be divided into mTOR dependent and mTOR non dependent pathways. In the former, the main molecular mechanism is to play the role of the Akt/mTOR signaling pathway and its downstream substrate, and to regulate translation and cell growth. In our previous work, we found that during the apoptosis of vascular endothelial cells induced by sera and growth factors, the small molecule compound 3G could induce Ingerin beta 4 protein phosphorylation and inducement, which could effectively induce the apoptosis of vascular endothelial cells. It is not clear that cells can play a role in inhibiting growth and become an effective tumor therapy drug. And whether it will affect the growth of normal cells is one of the key points for finding new drugs, and finding compounds that can specifically inhibit tumor cells can provide new prospects for drug development. Amine binding protein 1 (PEBP1), also known as Raf kinase suppressor, participates in the regulation of a variety of cell growth related signaling pathways such as MAPK, GPCR, NF- kappa B, GSK3 beta and other signaling pathways..PEBP1 can be involved in a variety of pathways that convert extracellular stimuli into different signals to maintain cell integrity and body balance. PEBP1 start Zi Jiaji in colon cancer patients This shows the potential importance of the abnormalities in the initiation of colon cancer. And in the latest studies, the direct interaction between PEBP1 and LC3 is verified, and PEBP1 combines the conservative LIR motif with LC3 and inhibits the autophagy of nutritional deprivation, and is mediated by the phosphorylation of PEBP1S153. The principles and techniques of chemical genetics are used to study the specific molecular mechanism of the small molecule 3G, which inhibits the growth of colon cancer cells, and determine its role in the regulation of autophagy and cell cycle, and provide new targets and effective tools for the treatment of colon cancer. 1. research methods have been made. Colon cancer Hct116 cells, human umbilical vein endothelial cells, human lung adenocarcinoma A549 cells, human cervical cancer HeLa cells, human prostate cancer PC3 cells, 2. inverted phase contrast microscope observation cell morphological changes, 3.SRB method to detect cell survival rate 4.Heochest staining, by fluorescence microscopy to observe the change of cell nuclear morphology, so as to judge the fine. Whether cell apoptosis 5.LDH (lactate dehydrogenase) detected cell necrosis and 6. flow cytometry to detect cell apoptosis and cell cycle 7. laser confocal microscopy detection of LC3-II distribution by 8.western blot detection of PARP and caspase-3 protein cutting levels, LC3-II and p62 protein expression levels, and Akt, mTOR, P70S6K, 4EBP1, phosphorylated water Study on the effect of small molecular compound on the progression of solid tumor and the formation of normal angiogenesis in the human fetal allantoic membrane model of 9. chick embryo. 1. the inhibitory effect of pyrazoloxane derivatives on the growth of various tumor cells was 1.1 SRB. The results showed that the small molecule compound 3G (1-10 mu M) could be significantly inhibited after a variety of tumor cells. The inhibitory effect of the compound on the colon cancer cell Hct116 cells was the strongest, and the cell morphology of the vascular endothelial cells, which did not affect the normal culture conditions under the same concentration, was observed by the.1.2 inversion phase contrast microscope, and the compound 3G (2.5-10 mu M) treated Hct1 16 cells 24h, and the cells gradually turned round. 3G treated A549. After the cell 24h, the cells had an obvious elongated.1.3 Heochest staining combined with the fluorescence microscope to observe the compound 3G (2.5-10 micron M) treatment of the tumor cell 24 h, and the nuclear agglutination was not obvious compared with the control group. The result of.1.4 flow cytometry showed that the compound 3G (5 micron M) treated Hct116 cell 24h, compared with the control group, the rate of apoptosis was no more than that of the control group. There was a significant increase of 1.5 Western-blot detection at 12h, 24h, and 48h 3G (5 M) may not induce PARP and caspase-3 cutting up up.1.6 LDH detection, compound 3G (10 micron) treatment of a variety of tumor cells 48, there is no significant difference in the activity of the culture liquid supernatant. Overregulation of autophagy and cell cycle inhibits the cell cycle 2.1 through flow cytometry that 3G (5 M) treatment of Hct116 cells 24h will cause G1 phase cell block.2.2 Western blot results, and the design of different time points using 3G (5 micron M) treatment Hct1 16 cells, compared with the control group, the expression significantly increased At the time of 48h, autophagic flow was obviously blocked by.2.3 immunocytochemical detection, and 3G (5 mu M) treated Hct116 cells 3H. Compared with the control group, LC3 appeared in Hct116 cells, and.2.4 Western blot results showed that after treating the cells with 3G (5 mu), compared with the control group, the 16 cells in a short period of time were phosphoric acid and phosphoric acid. The inhibition of.2.5 Western blot results showed that after Hct1 16 cells were treated with 3G (5 mu M), the phosphorylation of mTOR substrate P70S6K and 4EBP1 in Hct116 cells in a short time compared with the control group was suppressed.2.6 Western results showed that the phosphorous of 16 cells in a short time compared with the control group was compared with the control group. .2.7 chick embryo allantoic membrane human transplanted tumor model was suppressed after 3G treatment, compared with the control group, the development of solid tumor in the treatment group was obviously inhibited, and it did not affect the occurrence of normal blood vessels. Conclusion 1. small molecule compound 3G can significantly inhibit the survival of various human tumor cells, and the inhibitory production concentration dependence, among them, Hct116 thin The inhibitory effect of the cell is the strongest, and the.2. small molecule compound, 3G, which does not affect the normal culture medium, does not inhibit the growth of Hct1 16 cells by inducing apoptosis. The small molecule compound 3G can induce autophagy in a short period of time, and the autophagy is blocked at a long time, and the induction of autophagy can be induced. The role of cell cycle arrest. Its specific molecular mechanism is the phosphorylation of the PEBP1 S153 site in the short term, and the phosphorylation of the.PEBP1, realized by the Akt/mTOR signaling pathway, may be able to participate in the mediation of the mTOR dependent cell autophagic.3. small molecule compound 3G to inhibit the growth of solid tumor in the human embryo transfer tumor model of the chicken embryo. It shows that it has the prospect of developing tumor suppressor drugs.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.35
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