本文選題：缺糖/EBSS + Bcl-2抑制劑��； 參考：《吉林大學(xué)》2014年碩士論文

【摘要】：惡性腫瘤細胞能量代謝異常，出現(xiàn)能量代謝機制重建，“有氧糖酵解”（亦稱之為“Warburg效應(yīng)”）為顯著特征，表現(xiàn)為葡萄糖攝取量增高，糖酵解增加，胞外乳酸聚積。糖酵解途徑為腫瘤細胞提供ATP，還為腫瘤細胞的生存、侵襲提供優(yōu)勢。眾多學(xué)者對惡性腫瘤糖酵解特點和機制進行了大量的研究，力求找到治療惡性腫瘤新途徑。近年來，探索糖剝奪或阻斷糖酵解途徑的策略正備受關(guān)注。 目前認為，Bcl-2家族蛋白在凋亡通路調(diào)節(jié)中發(fā)揮關(guān)鍵的作用。研究表明，缺糖引起的凋亡與Bcl-2家族蛋白調(diào)控密切相關(guān)。葡萄糖缺乏時，糖原合成酶激酶3β（glycogen synthesis kinase3β，GSK3β）磷酸化Bcl-2家族抗凋亡蛋白Mcl-1，并靶向Mcl-1使之通過蛋白酶體途徑降解。缺糖促使激活單磷酸腺苷活化蛋白激酶（Adenosine monophosphate(AMP)-activated protein kinase，AMPK），誘導(dǎo)Bim轉(zhuǎn)錄，也可造AMPK依賴性哺乳動物雷帕霉素靶蛋白（mammalian target ofrapamycin，mTOR）失活，抑制Mcl-1轉(zhuǎn)錄。此外，缺糖還可通過AMPK引起腫瘤抑制基因p53的轉(zhuǎn)錄和蛋白穩(wěn)定，激活某些Bcl-2家族促凋亡蛋白如Bax、Puma和Noxa的轉(zhuǎn)錄。還有實驗結(jié)果顯示，缺糖還促使細胞激活ER應(yīng)激，調(diào)節(jié)Bcl-2家族蛋白活性和轉(zhuǎn)錄。糖代謝可能參與了Bcl-2家族蛋白在凋亡通路的調(diào)控，糖分解代謝在轉(zhuǎn)錄水平和轉(zhuǎn)錄后水平調(diào)控Bcl-2家族蛋白的功能。 BH3-only蛋白與Bcl-2家族抗凋亡蛋白特異性結(jié)合抑制其發(fā)揮作用。Bcl-2家族蛋白都具有BH3結(jié)構(gòu)域，抗凋亡蛋白和促凋亡蛋白正是通過這個共同的結(jié)構(gòu)域形成異源二聚體，相互制約。BH3-only蛋白通過干擾或者促成這些二聚體和多聚體的形成和穩(wěn)定，調(diào)控細胞生存和凋亡。Bcl-2在腫瘤細胞往往高表達，使細胞逃逸凋亡。Bcl-2抑制劑S1是分子靶向治療藥物，通過模擬BH3-only蛋白，雙靶點抑制Bcl-2和Mcl-1，激活Bax/Bak，實現(xiàn)誘導(dǎo)腫瘤細胞凋亡。課題組前期研究表明，在黑色素瘤B16細胞、卵巢癌細胞SKOV3和神經(jīng)膠質(zhì)瘤U251細胞中，S1能有效地誘導(dǎo)細胞凋亡。 同時缺糖和S1都能誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激和自噬，這種適應(yīng)性反應(yīng)對癌細胞可能有保護作用，影響癌細胞對缺糖和S1誘導(dǎo)凋亡的敏感性，抑制這種適應(yīng)性反應(yīng)，可能為腫瘤治療提供了靶點。 目前發(fā)現(xiàn)，腫瘤細胞的治療是通過多靶點、多因素、多環(huán)節(jié)的調(diào)控，一個基因突變不足以使細胞死亡。所以當(dāng)藥物作用于一個靶點時，往往不足以達到使癌細胞致死的殺傷力，只有共同作用于多個靶點時，才有可能達到更好的治療效果。為了使S1更有效的發(fā)揮作用，我們的研究根據(jù)腫瘤細胞高度依賴葡萄糖生存的特點，采用Earle's平衡鹽緩沖液（EBSS）模擬缺糖環(huán)境，和S1共同作用Hela細胞，發(fā)現(xiàn)缺糖增強了S1誘導(dǎo)Hela細胞凋亡敏感性。同時測得EBSS和S1共同作用誘導(dǎo)Hela細胞發(fā)生內(nèi)質(zhì)網(wǎng)應(yīng)激和自噬程度加重，我們在細胞中加入自噬抑制劑，結(jié)果顯示，Hela細胞凋亡的敏感性進一步增強。說明自噬在缺糖和S1對Hela細胞的損傷的過程中具有一定的保護作用。 方法 （1）MTT法檢測EBSS和S1作用的Hela細胞生存率。 （2）倒置顯微鏡觀察EBSS和S1作用的Hela細胞生長狀態(tài)。 （3）Hoechst33342染色觀察EBSS和S1作用的Hela細胞核凋亡情況。 （4）Western blot方法檢測線粒體凋亡相關(guān)蛋白Cyto C、Caspase-3、PARP-1，Bcl-2家族蛋白，以及對Bcl-2家族蛋白有調(diào)控作用的因子mTOR、p70S6K、p53的變化；檢測內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志性蛋白PDI、GRP78蛋白表達變化以及內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)蛋白PERK、CHOP、IRE1、JNK等表達變化；檢測自噬相關(guān)蛋白LC3、Atg12-Atg5、P62、Beclin1表達變化。 （5）共聚焦顯微鏡觀察細胞內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志性蛋白GRP78熒光強度變化；觀察細胞自噬標(biāo)志性蛋白LC3點狀聚集變化。 （6）LysoTracker染色，共聚焦顯微鏡觀察EBSS和S1作用的Hela細胞中溶酶體的變化。 結(jié)果 （1）缺糖增強S1對Hela細胞生長的抑制作用。 MTT檢測結(jié)果表明EBSS（缺糖）和S1都能降低Hela細胞的生存率，隨著EBSS作用時間延長，S1劑量增加及作用時間延長，生存率逐漸降低；同時倒置顯微鏡下觀察細胞，細胞密度降低，細胞收縮變圓。當(dāng)EBSS和S1共同作用Hela細胞時，結(jié)果顯示，與單獨作用相比，存活率顯著下降，細胞密度明顯降低。說明缺糖增強S1對Hela細胞生長的抑制作用。 （2）缺糖增強S1誘導(dǎo)的Hela細胞凋亡。 Hoechst33342染色觀察到EBSS和S1都分別引起Hela細胞核發(fā)生固縮、碎裂，染色增強，二者共同作用后，比單獨作用變化更加顯著。Western blot結(jié)果顯示，EBSS和S1作用的Hela細胞與對照組相比，凋亡相關(guān)蛋白Cyto C、Caspase-3、PARP-1表達顯著增加，Bcl-2家族促凋亡蛋白Bax、Bim、Noxa明顯增加，抗凋亡蛋白Bcl-2、Mcl-1顯著減少；對Bcl-2家族蛋白有調(diào)控作用的因子mTOR、p70S6K磷酸化程度降低，p53表達增加。當(dāng)EBSS和S1二者共同作用后，比單獨作用變化更明顯。 EBSS和S1分別單獨作用能夠抑制抗凋亡蛋白Bcl-2、Mcl-1的蛋白表達和活性，促進促凋亡蛋白Bax、Bim、Noxa的表達和活化，從而誘導(dǎo)Hela細胞內(nèi)的Cyto C釋放以及Caspase-3、PARP-1活化，導(dǎo)致Hela細胞凋亡。當(dāng)EBSS和S1共同作用后，Hela細胞凋亡增加。 （3）缺糖增強S1誘導(dǎo)的Hela細胞內(nèi)質(zhì)網(wǎng)應(yīng)激。 激光共聚焦顯微鏡觀察內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志蛋白GRP78熒光表達變化。與對照組相比，EBSS和S1單獨作用的Hela細胞中GRP78的熒光強度明顯增加，，聯(lián)合作用后，比單獨作用變化更明顯。Western blot檢測，EBSS和S1分別單獨作用能夠誘導(dǎo)Hela細胞內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志性蛋白GRP78、PDI表達上調(diào)，說明缺糖和S1均能引起內(nèi)質(zhì)網(wǎng)應(yīng)激。進一步Western blot檢測表明，內(nèi)質(zhì)網(wǎng)應(yīng)激相關(guān)蛋白p-PERK、IRE1表達上調(diào)，未折疊蛋白反應(yīng)（unfolded protein response，UPR）信號通路下游蛋白p-eIF2α、ATF4、CHOP、p-JNK表達增加，說明在Hela細胞中PERK通路和IRE1通路被活化。當(dāng)EBSS和S1聯(lián)合作用后，上述內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng)相關(guān)蛋白表達變化程度增強，可能影響B(tài)cl-2家族蛋白的表達和活性，調(diào)控凋亡。 （4）缺糖增強S1誘導(dǎo)的Hela細胞自噬。 內(nèi)質(zhì)網(wǎng)應(yīng)激在誘導(dǎo)細胞凋亡的同時，也誘導(dǎo)細胞的自噬。激光共聚焦顯微鏡觀察自噬標(biāo)志蛋白LC3熒光表達變化，與對照組相比，EBSS和S1單獨作用的Hela細胞中LC3點狀聚集都明顯增多；聯(lián)合作用后，程度加重。LysoTracker染色，觀察到EBSS和S1單獨作用的Hela細胞中溶酶體有一定程度增加；聯(lián)合作用后，與單獨作用組相比，溶酶體顯著增加。Western blot檢測，EBSS和S1分別單獨作用明顯促進Hela細胞自噬相關(guān)蛋白表達變化，P62表達減少，LC3-Ⅱ蛋白水平增加，表示有自噬發(fā)生；聯(lián)合作用與單獨作用相比蛋白表達有更加顯著的變化，說明自噬程度加強。 （5）自噬抑制劑阻斷缺糖和S1共同作用誘導(dǎo)的Hela細胞自噬，進一步增強細胞凋亡。 MTT結(jié)果表明，自噬抑制劑進一步加強了EBSS和S1共同作用對Hela細胞增殖的抑制作用；LysoTracker染色，觀察到CQ使EBSS和S1共同作用的Hela細胞中溶酶體有一定程度減少；Western blot結(jié)果顯示，自噬相關(guān)蛋白表達發(fā)生變化，凋亡相關(guān)蛋白表達增加，表明自噬被抑制，細胞凋亡敏感性增強。 結(jié)論 缺糖能夠明顯抑制Hela細胞的生長，并通過調(diào)節(jié)Bcl-2家族蛋白，誘導(dǎo)細胞凋亡；Bcl-2抑制劑S1雙靶點抑制Bcl-2和Mcl-1，誘導(dǎo)凋亡。兩者共同作用，缺糖增加了S1誘導(dǎo)Hela細胞凋亡的敏感性，抑制自噬，凋亡程度進一步增加。
[Abstract]:The energy metabolism of malignant tumor cells is abnormal, and the energy metabolism mechanism is rebuilt. "Aerobic glycolysis" (also called "Warburg effect") is characterized by high glucose uptake, increased glycolysis, and extracellular lactate accumulation. Glycolytic pathway provides ATP for tumor cells, and also provides advantages for tumor cells to survive and invasion. Many scholars have done a lot of research on the characteristics and mechanisms of glycolysis for malignant tumors, and strive to find new ways to treat malignant tumors. In recent years, the strategy of exploring sugar deprivation or blocking glycolysis is being paid much attention.
It is believed that Bcl-2 family proteins play a key role in the regulation of apoptosis pathway. Studies have shown that the apoptosis induced by glucose deficiency is closely related to the regulation of Bcl-2 family proteins. When glucose deficiency, the glycogen synthetase kinase 3 beta (glycogen synthesis kinase3 beta, GSK3 beta) phosphorylates the Bcl-2 family anti apoptotic protein Mcl-1, and targets Mcl-1 to pass eggs Glucose deficiency promotes activation of Adenosine monophosphate (AMP) -activated protein kinase, AMPK, induces Bim transcription, and can also make the AMPK dependent mammal rapamycin target protein (mammalian target ofrapamycin,) deactivation and inhibits transcription. The transcriptional and protein stability of the tumor suppressor gene p53 activates the transcription of some Bcl-2 family Pro apoptotic proteins such as Bax, Puma and Noxa. Experimental results show that glucose deficiency also activates ER stress and regulates the activity and transcription of Bcl-2 family proteins. Sugar metabolism may be involved in the regulation of Bcl-2 family proteins in the apoptotic pathway and glycometabolism Transcriptional and post transcriptional levels regulate the function of Bcl-2 family proteins.
The specific binding of BH3-only protein to the anti apoptotic protein of the Bcl-2 family inhibits the action of the.Bcl-2 family proteins with the BH3 domain. The anti apoptotic protein and the apoptotic protein are the formation of the allogeneic two polymer through this common domain, which restricts the formation of.BH3-only proteins by interfering or contributing to the formation of these two polymers and polymers. And the stability, regulation of cell survival and apoptosis of.Bcl-2 in tumor cells often high expression, make cells escape apoptosis.Bcl-2 inhibitor S1 is a molecular targeting therapy drug, through the simulation of BH3-only protein, double target inhibition of Bcl-2 and Mcl-1, activation of Bax/Bak, to induce tumor cell apoptosis. S1 can effectively induce apoptosis in nested cancer cells SKOV3 and glioma U251 cells.
At the same time, both glucose deficiency and S1 can induce endoplasmic reticulum stress and autophagy. This adaptive response may have protective effects on cancer cells, which may affect the sensitivity of cancer cells to glucose deficiency and S1 induced apoptosis, and inhibit this adaptive response, which may provide targets for cancer treatment.
At present, it is found that the treatment of tumor cells is through multiple targets, multiple factors and multiple links. One gene mutation is not enough to cause the death of the cells. So when the drug acts on a target, it is often not enough to kill the killing of cancer cells. It is possible to achieve better therapeutic effect only when the target is used together in multiple targets. In order to make S1 more effective, our study was based on the high dependence of the tumor cells on glucose survival, using the Earle's balanced salt buffer solution (EBSS) to simulate the glucose deficiency environment and the co action of S1 to Hela cells. It was found that glucose deficiency enhanced the S1 induced apoptosis sensitivity of Hela cells. Meanwhile, the common action of EBSS and S1 induced Hela cells to induce the occurrence of Hela cells. Endoplasmic reticulum stress and autophagy are aggravated, and autophagic inhibitors are added to the cells. The results show that the sensitivity of Hela cell apoptosis is further enhanced. It shows that autophagy has a protective effect in the process of impaired glucose and S1's damage to Hela cells.
Method
(1) MTT assay was used to detect the Hela cell survival rate of EBSS and S1.
(2) the growth state of Hela cells treated with EBSS and S1 was observed by inverted microscope.
(3) Hoechst33342 staining was used to observe the apoptosis of Hela cells treated by EBSS and S1.
(4) Western blot method was used to detect the mitochondrial apoptosis related protein Cyto C, Caspase-3, PARP-1, Bcl-2 family proteins, and the changes in mTOR, p70S6K, p53, the regulation of Bcl-2 family proteins, and the expression of endoplasmic reticulum stress marker proteins and endoplasmic reticulum stress related proteins. The expression of autophagy related proteins LC3, Atg12-Atg5, P62 and Beclin1 was detected.
(5) confocal microscopy was used to observe the changes of the fluorescence intensity of the endoplasmic reticulum stress marker protein GRP78, and to observe the change of dot aggregation of the autophagy marker protein LC3.
(6) LysoTracker staining and confocal microscopy were used to observe the changes of lysosomes in EBSS and S1 Hela cells.
Result
(1) glucose deprivation enhances the inhibitory effect of S1 on the growth of Hela cells.
The results of MTT test showed that both EBSS (sugar deficiency) and S1 could reduce the survival rate of Hela cells. With the prolongation of the time of EBSS action, the increase of S1 dose and the prolongation of the action time and the gradual decrease of the survival rate. At the same time, the cell density decreased and the cell contraction became round under the inverted microscope. When EBSS and S1 co acted on Hela cells, the results showed, and the results showed alone. Compared with the control group, the survival rate decreased significantly and cell density decreased significantly, indicating that lack of sugar enhanced the inhibitory effect of S1 on the growth of Hela cells.
(2) the lack of sugar enhanced the apoptosis of Hela cells induced by S1.
Hoechst33342 staining showed that both EBSS and S1 caused Hela nucleus contraction, fragmentation, and staining enhancement. After the combination of the two, the.Western blot results showed that the Hela cells acting on EBSS and S1 were compared with the control group, and the apoptosis related protein Cyto C, Caspase-3, expression increased significantly. Apoptotic protein Bax, Bim, Noxa were significantly increased, anti apoptotic protein Bcl-2, Mcl-1 significantly decreased, and Bcl-2 family protein has a regulated factor mTOR, p70S6K phosphorylation level decreased, p53 expression increased. When EBSS and S1 two together, more obvious than the individual action.
EBSS and S1 separately inhibit the expression and activity of anti apoptotic protein Bcl-2, Mcl-1, promote the expression and activation of apoptotic protein Bax, Bim, Noxa, and induce Cyto C release in Hela cells and Caspase-3, PARP-1 activation, resulting in apoptosis.
(3) glucose deprivation enhances the endoplasmic reticulum stress induced by S1 in Hela cells.
The fluorescence intensity of endoplasmic reticulum stress marker protein GRP78 was observed by laser confocal microscopy. Compared with the control group, the fluorescence intensity of GRP78 was significantly increased in the Hela cells of EBSS and S1 alone. After the combination, the.Western blot detection was more obvious than the single action change. The individual action of EBSS and S1 could induce the endoplasmic reticulum of Hela cells respectively. The expression of GRP78 and PDI was up-regulated, indicating that both glucose deficiency and S1 could cause endoplasmic reticulum stress. Further Western blot detection showed that the expression of endoplasmic reticulum stress related protein p-PERK, IRE1 expression up, and unfolded protein reaction (unfolded protein response, UPR) PERK pathway and IRE1 pathway are activated in the cell. When the EBSS and S1 are combined, the expression of the stress response related proteins in the endoplasmic reticulum is enhanced, which may affect the expression and activity of Bcl-2 family proteins and regulate the apoptosis.
(4) glucose deficiency enhanced autophagy induced by S1 in Hela cells.
Endoplasmic reticulum stress also induced autophagy at the same time of inducing cell apoptosis. Laser confocal microscopy observed the changes in autophagy LC3 fluorescent expression. Compared with the control group, the LC3 point aggregation of LC3 in the Hela cells of EBSS and S1 was significantly increased; the degree of.LysoTracker staining was aggravated and EBSS and S1 single were observed after the combined action. The lysosomes in the only Hela cells increased to a certain extent. After the combined action, the lysosomes significantly increased the.Western blot detection compared with the single action group. The separate action of EBSS and S1 promoted the expression of autophagy related protein in Hela cells, the expression of P62 decreased, and the level of LC3- II protein increased, indicating the occurrence of autophagy; combined action. Compared with the single action, the protein expression had a more significant change, indicating that the degree of autophagy was strengthened.
(5) autophagy inhibitor blocked the autophagy of Hela cells induced by the combination of glucose and S1, and further enhanced cell apoptosis.
MTT results showed that the autophagy inhibitor further enhanced the inhibitory effect of EBSS and S1 on the proliferation of Hela cells. LysoTracker staining showed that the lysosomes in Hela cells with the joint action of EBSS and S1 decreased to a certain extent, and Western blot results showed that the expression of autophagy related egg white was changed and the expression of apoptosis related proteins increased. Addition showed that autophagy was inhibited and the sensitivity of apoptosis increased.
conclusion
Sugar deficiency can obviously inhibit the growth of Hela cells and induce apoptosis by regulating Bcl-2 family proteins. The double target of Bcl-2 inhibitor S1 inhibits Bcl-2 and Mcl-1 and induces apoptosis. Both the two effects can increase the sensitivity of S1 induced apoptosis of Hela cells, inhibit autophagy and increase the degree of death.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R737.33

【共引文獻】

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