本文選題：b-AP15 + 去泛素化酶抑制劑�。� 參考：《廣州醫(yī)科大學(xué)》2017年碩士論文

【摘要】：背景與目的隨著部分患者的病情進(jìn)展為致命和不能治愈的轉(zhuǎn)移性去勢(shì)抵抗性前列腺癌(castrate-resistant prostate cancer,CRPC),前列腺癌(Prostate Cancer,PCa)仍然是男性癌癥相關(guān)死亡的主要原因。泛素-蛋白酶體系統(tǒng)(Ubiquitin-Proteasome System,UPS)是細(xì)胞蛋白質(zhì)高度特異和選擇性降解的途徑,通過(guò)調(diào)節(jié)底物泛素化和去泛素化之間的動(dòng)態(tài)平衡來(lái)掌控大多數(shù)蛋白質(zhì)的命運(yùn)。近期研究表明去泛素化酶(Deubiquitinases,DUBs)已成為抗癌治療的新靶點(diǎn),它可以調(diào)節(jié)多種細(xì)胞過(guò)程,包括細(xì)胞周期控制,DNA損傷反應(yīng)和修復(fù),凋亡,染色質(zhì)修飾以及各種信號(hào)轉(zhuǎn)導(dǎo)途徑。硼替佐米(bortezomib/Velcade)是20S蛋白酶體的抑制劑,已被美國(guó)FDA批準(zhǔn)用于治療臨床多發(fā)性骨髓瘤和淋巴瘤等疾病并取得良好的療效,證實(shí)了泛素蛋白酶體系統(tǒng)是腫瘤治療的一個(gè)重要靶點(diǎn),這也證明UPS組份是一種新型的有效抗腫瘤分子靶標(biāo),吸引了研究者對(duì)蛋白酶體系統(tǒng)進(jìn)行更深入的研究和探索,從而尋求更有治療前景的抗腫瘤藥物。雄激素受體(Androgen Receptor,AR)與前列腺癌的發(fā)生發(fā)展密切相關(guān),它是一種雄激素依賴的轉(zhuǎn)錄因子,屬于核受體超家族。在前列腺癌中通常能觀察到AR基因的擴(kuò)增和突變,AR信號(hào)通路支配前列腺癌的存活,增殖和生長(zhǎng)。我們課題組前期研究發(fā)現(xiàn)去泛素化酶USP14可以穩(wěn)定并調(diào)節(jié)AR,抑制USP14可以促進(jìn)AR泛素化降解從而抑制AR依賴前列腺癌細(xì)胞增殖,但對(duì)AR非依賴前列腺癌細(xì)胞沒(méi)有影響。一個(gè)新型的小分子b-AP15已被鑒定為19S蛋白酶體USP14/UC HL5(DUBs)的抑制劑,能誘導(dǎo)多種人類(lèi)腫瘤細(xì)胞系的增殖抑制和細(xì)胞凋亡。本研究我們擬進(jìn)一步探討同時(shí)抑制USP14和UCHL5是否對(duì)AR產(chǎn)生協(xié)同調(diào)控作用以及對(duì)AR依賴與非依賴前列腺癌的抗腫瘤效應(yīng)。根據(jù)我們的實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)b-AP15可以促進(jìn)AR的泛素化降解,但這種作用主要是通過(guò)USP14的功能抑制,而與UCHL5的功能調(diào)控?zé)o關(guān),并發(fā)現(xiàn)b-AP15通過(guò)誘導(dǎo)UPS的抑制、caspases活化、內(nèi)質(zhì)網(wǎng)應(yīng)激與氧化應(yīng)激的產(chǎn)生引起AR依賴和非依賴性前列腺癌細(xì)胞的增殖抑制和凋亡。實(shí)驗(yàn)方法1、細(xì)胞活力檢測(cè):采用MTS法和CCK-8法檢測(cè)b-AP15對(duì)前列腺癌和正常前列腺上皮細(xì)胞活力的影響。2、克隆形成實(shí)驗(yàn):克隆形成實(shí)驗(yàn)的處理方法同上。用光學(xué)顯微鏡計(jì)數(shù)大于10個(gè)細(xì)胞的克隆數(shù)。3、細(xì)胞凋亡情況檢測(cè):采用Annexin V-FITC/Propidium iodide(PI)標(biāo)記死亡細(xì)胞用流式細(xì)胞儀分析細(xì)胞凋亡情況以及熒光顯微鏡觀察并拍照記錄細(xì)胞形態(tài)學(xué)變化。4、Si RNA轉(zhuǎn)染:敲除USP14和UCHL5檢測(cè)AR的表達(dá)。5、Co-IP聯(lián)合Western bolt:檢測(cè)相關(guān)蛋白的表達(dá)。6、線粒體膜電位完整性檢測(cè):采用羅丹明123染色法用流式細(xì)胞儀分析。7、活性氧檢測(cè):采用10μM DCFH-DA對(duì)樣本進(jìn)行染色,隨后用流式細(xì)胞儀分析。8、實(shí)時(shí)熒光定量PCR:根據(jù)Takara試劑盒說(shuō)明書(shū)操作,擴(kuò)增結(jié)束后得到各檢測(cè)基因的Cq值?9、裸鼠載體實(shí)驗(yàn):SPF級(jí)裸鼠右側(cè)腋皮下接種PC-3細(xì)胞,b-AP15腹腔注射給藥,觀察裸鼠體重和腫瘤體積變化。10、免疫組化:檢測(cè)腫瘤組織中的蛋白表達(dá)情況。實(shí)驗(yàn)結(jié)果1、b-AP15對(duì)前列腺癌細(xì)胞增殖的影響不同處理濃度(0-5μM)的b-AP15作用于AR依賴前列腺癌細(xì)胞LNCa P,22Rv1,AR非依賴前列腺癌細(xì)胞PC-3,DU145和前列腺基質(zhì)細(xì)胞WPMY-1 24,48,72 h后,都有不同程度抑制增殖作用,表明b-AP15對(duì)前列腺癌細(xì)胞和正常細(xì)胞的抑制作用沒(méi)有明顯的細(xì)胞選擇性。此外,克隆形成的結(jié)果顯示b-AP15抑制了LNCa P和PC-3細(xì)胞集落的形成。2、b-AP15誘導(dǎo)細(xì)胞周期停滯不同濃度的b-AP15(0,0.5,1,2μM)作用于LNCa P和PC-3細(xì)胞24h后進(jìn)行細(xì)胞周期分析。結(jié)果表明隨著b-AP15濃度的增加,兩個(gè)細(xì)胞系的細(xì)胞周期都停滯在G0/G1期。Western blot結(jié)果顯示,b-AP15可顯著降低細(xì)胞周期蛋白cyclin D1,CDK6,CDK4,C DK2和p-Rb(G1期到S期的標(biāo)記蛋白)的表達(dá),并使抑制cyclin-CDK功能的抑癌基因p27表達(dá)增加。3、b-AP15誘導(dǎo)caspase依賴的細(xì)胞凋亡b-AP15作用于LNCa P和PC-3細(xì)胞后Annexin-V/PI陽(yáng)性率顯著增加,出現(xiàn)細(xì)胞凋亡的形態(tài)學(xué)變化。Western blot結(jié)果顯示,兩個(gè)細(xì)胞系活化的caspase-3,-8,-9都顯著升高,PARP出現(xiàn)切割帶。4、b-AP15誘導(dǎo)的細(xì)胞凋亡與線粒體功能障礙有關(guān)細(xì)胞凋亡主要通過(guò)內(nèi)源性和外源性兩種途徑調(diào)控,而內(nèi)源性途徑又稱為線粒體途徑。通過(guò)羅丹明123染色法,流式細(xì)胞儀進(jìn)行檢測(cè)發(fā)現(xiàn)b-AP15能引起線粒體跨膜電位下降。對(duì)LNCa P和PC-3兩種細(xì)胞系進(jìn)行濃度和時(shí)間依賴處理,結(jié)果表明b-AP15引起抗凋亡蛋白(Bcl-2)的表達(dá)下調(diào),而促凋亡蛋白(Bim,Bax,Noxa)則顯著增加。此外,隨著膜通透性改變,釋放至細(xì)胞質(zhì)中的促凋亡因子(細(xì)胞色素C)和細(xì)胞凋亡誘導(dǎo)因子(AIF)水平也顯著增加。5、b-AP15作用后能誘導(dǎo)ROS產(chǎn)生,抗氧化劑N-乙酰半胱氨酸(NAC)可逆轉(zhuǎn)b-AP15誘導(dǎo)的凋亡。6、b-AP15可明顯抑制LNCa P和PC-3細(xì)胞的蛋白酶體功能和雄激素受體(AR)的表達(dá),產(chǎn)生內(nèi)質(zhì)網(wǎng)應(yīng)激。低濃度的b-AP15即能引起泛素化蛋白(Ub-prs)的聚集,蛋白酶體功能抑制早于細(xì)胞凋亡的產(chǎn)生,說(shuō)明b-AP15是通過(guò)抑制UPS的功能誘導(dǎo)細(xì)胞凋亡。研究發(fā)現(xiàn)b-AP15能產(chǎn)生內(nèi)質(zhì)網(wǎng)應(yīng)激以及抑制雄激素受體(AR)的表達(dá),通過(guò)RT-PCR和免疫共沉淀實(shí)驗(yàn)檢測(cè)發(fā)現(xiàn)AR的抑制是通過(guò)泛素化降解而不是基因轉(zhuǎn)錄水平。另外,用UCHL5的si RNA轉(zhuǎn)染LNCa P細(xì)胞,Western blot檢測(cè)AR的表達(dá),結(jié)果顯示敲除UCHL5并不能抑制AR,結(jié)合前期實(shí)驗(yàn)結(jié)果說(shuō)明b-AP15對(duì)AR的抑制主要是通過(guò)抑制USP14發(fā)揮的作用。7、b-AP15對(duì)BALB/c裸鼠異種移植瘤的影響與對(duì)照組比較,結(jié)果顯示b-AP15治療組的腫瘤體積和腫瘤重量明顯降低,兩組之間裸鼠體重?zé)o統(tǒng)計(jì)學(xué)差異。免疫組化染色后發(fā)現(xiàn)b-AP15處理的腫瘤組織中,蛋白酶體泛素化底物蛋白聚集,p27以及活化的caspase-3表達(dá)增加。檢測(cè)兩組裸鼠的心肌,肝臟以及腎臟組織中肌酸激酶,谷丙轉(zhuǎn)氨酶和肌酐的指標(biāo),結(jié)果表明b-AP15并對(duì)心,肝,腎功能沒(méi)有影響,說(shuō)明b-AP15的毒性作用是可控的,對(duì)前列腺癌具有廣闊的治療前景。結(jié)論1、b-AP15可以誘導(dǎo)體內(nèi)外雄激素受體依賴和非依賴的前列腺癌細(xì)胞凋亡。
[Abstract]:Background and objective with the progression of some patients to fatal and incurable metastatic metastatic castration resistant prostate cancer (castrate-resistant prostate cancer, CRPC), and prostate cancer (Prostate Cancer, PCa) remains the main cause of cancer related deaths in men. The ubiquitin proteasome system (Ubiquitin-Proteasome System, UPS) is fine. Deubiquitinases (DUBs) has become a new target for anti-cancer therapy, which can regulate a variety of cellular processes, including cell cycle control. DNA damage reaction and repair, apoptosis, chromatin modification and various signal transduction pathways. Borteg Zomi (bortezomib/Velcade) is an inhibitor of 20S proteasome. It has been approved by American FDA for the treatment of clinical multiple myeloma and lymphoma, and has achieved good therapeutic effect. It has been proved that the ubiquitin proteasome system is a tumor treatment. The important target is that the UPS component is a new type of effective anti-tumor molecular target, which attracts researchers to study and explore the proteasome system more deeply, so as to seek a more promising antitumor drug. The Androgen Receptor (AR) is closely related to the development of prostate cancer. It is a kind of prostatic cancer. Androgen dependent transcription factors, belonging to the nuclear receptor superfamily. In prostate cancer, the amplification and mutation of the AR gene are usually observed. The AR signaling pathway dominates the survival, proliferation, and growth of the prostate cancer. Our previous study found that the deubiquitinase USP14 could stabilize and regulate the node AR, and the inhibition of USP14 could promote AR ubiquitination degradation from the prostate cancer. The inhibition of AR dependence on the proliferation of prostate cancer cells has no effect on AR non dependent prostate cancer cells. A new small molecule b-AP15 has been identified as an inhibitor of 19S proteasome USP14/UC HL5 (DUBs), which can induce proliferation inhibition and cell apoptosis in various human tumor cell lines. This study intends to further explore the simultaneous inhibition of USP14. Whether or not UCHL5 has a synergistic effect on AR and the antitumor effect on AR dependent and non dependent prostate cancer. According to our experimental results, it is found that b-AP15 can promote the ubiquitination of AR, but this effect is mainly through the function inhibition of USP14 and not related to the function control of UCHL5, and it is found that b-AP15 can inhibit UPS by inducing the inhibition of UPS, Caspases activation, endoplasmic reticulum stress and oxidative stress induced proliferation inhibition and apoptosis of AR dependent and non dependent prostate cancer cells. Experimental methods 1, cell viability detection: the effects of b-AP15 on the activity of prostate cancer and normal prostate epithelial cells by MTS and CCK-8 methods,.2, cloning and formation experiments: cloning and formation experiments The method of treatment was same. The number of clones more than 10 cells was counted by the optical microscope.3, the apoptosis was detected. The apoptotic cells were labeled with Annexin V-FITC/Propidium iodide (PI) and the cell apoptosis was analyzed by flow cytometry and the morphological changes of.4 were recorded by the fluorescence microscope and Si RNA transfected: USP14 and UCHL5 were knocked out. Detection of AR expression.5, Co-IP combined with Western bolt: to detect the expression of related protein.6, mitochondrial membrane potential integrity detection: using Luo Danming 123 staining method to analyze.7 with flow cytometer, reactive oxygen species detection: 10 u M DCFH-DA to stain samples, and then flow cytometry analysis.8, real time fluorescent quantitative PCR: according to Takara kit said After the operation, the Cq value of each detection gene was obtained after the end of amplification? 9, the carrier experiment in nude mice: PC-3 cells were inoculated subcutaneously in the right axilla of the SPF nude mice and b-AP15 was injected intraperitoneally to observe the changes of body weight and tumor volume of nude mice.10, immunohistochemistry: detection of the protein table in the tumor tissue. Experimental results were 1, b-AP15 proliferation of prostate cancer cells. The effect of b-AP15 on AR dependent prostate cancer cells LNCa P, 22Rv1, AR is not dependent on the prostate cancer cell PC-3, DU145 and the WPMY-1 24,48,72 h of the prostatic stromal cells, AR dependent on the inhibition of the proliferation of prostate cancer cells and normal cells. It shows that there is no obvious cell selection for the inhibition of prostate cancer cells and normal cells. In addition, the results of clone formation showed that b-AP15 inhibited the formation of LNCa P and PC-3 cell colony formation.2, and b-AP15 induced cell cycle Stagnation with different concentrations of b-AP15 (0,0.5,1,2 u M) acting on the cell cycle analysis after LNCa P and PC-3 cells. The results showed that the cell cycle of the two cell lines stagnated with the increase of concentration. The results of G0/G1 phase.Western blot show that b-AP15 can significantly reduce the expression of cell cycle protein cyclin D1, CDK6, CDK4, C DK2 and p-Rb (G1 phase to the marker protein), and increase the expression of the tumor suppressor gene that inhibits the function of the cell. .Western blot results showed that the activation of Caspase-3, -8, -9 in two cell lines increased significantly, and PARP appeared in the cleavage band.4. B-AP15 induced apoptosis related to mitochondrial dysfunction mainly regulated by endogenous and exogenous pathways, while endogenous pathways were regulated by endogenous and exogenous pathways. It was also called the mitochondrial pathway. Through the Luo Danming 123 staining method, the flow cytometry detected that b-AP15 could cause the mitochondrial transmembrane potential decline. The concentration and time dependence of the LNCa P and PC-3 cell lines were treated with concentration and time dependence. The results showed that the b-AP15 induced the down regulation of the anti apoptotic protein (Bcl-2), while the apoptotic protein (Bim, Bax, Noxa) was significant. In addition, with the change of membrane permeability, the level of apoptosis inducing factor (cytochrome C) and apoptosis inducible factor (AIF) released into cytoplasm also increased.5, and ROS produced after b-AP15 action. The antioxidant N- acetylcysteine (NAC) could reverse b-AP15 induced apoptosis.6. B-AP15 could obviously inhibit LNCa P and eggs. The expression of white enzyme body function and androgen receptor (AR) produces endoplasmic reticulum stress. Low concentration of b-AP15 can cause the aggregation of ubiquitin protein (Ub-prs). The inhibition of proteasome function is earlier than the production of cell apoptosis. It shows that b-AP15 can induce apoptosis by inhibiting the function of UPS. The study found that b-AP15 can produce endoplasmic reticulum stress and inhibit male. The expression of hormone receptor (AR) was detected by RT-PCR and immunoprecipitation assay. The inhibition of AR was mediated by ubiquitination and not gene transcription. In addition, LNCa P cells were transfected with UCHL5 Si RNA. Western blot was used to detect AR expression. The effect of the system was mainly by inhibiting the effect of USP14 on.7. The effect of b-AP15 on xenotransplantation in BALB/c nude mice was compared with that of the control group. The results showed that the tumor volume and tumor weight of the b-AP15 group decreased obviously, and there was no statistical difference between the two groups of nude mice. The proteasome was ubiquitous in the b-AP15 treated tumor tissues after immunohistochemical staining. The aggregation of vegetated substrate protein, p27 and activated caspase-3 expression increased. The indexes of creatine kinase, alanine transaminase and creatinine in two groups of nude mice were detected. The results showed that b-AP15 had no effect on the heart, liver and kidney function, indicating that the toxic effect of b-AP15 was controllable and has a broad treatment for prostate cancer. Conclusion. 1, b-AP15 can induce androgen receptor dependent and independent prostate cancer cell apoptosis in vivo and in vitro.
【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R737.25

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