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,通過調(diào)節(jié)底物泛素化和去泛素化之間的動態(tài)平衡來掌控大多數(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信號通路支配前列腺癌的存活,增殖和生長。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AR非依賴前列腺癌細(xì)胞沒有影響。一個新型的小分子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)一步探討同時抑制USP14和UCHL5是否對AR產(chǎn)生協(xié)同調(diào)控作用以及對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:采用MTS法和CCK-8法檢測b-AP15對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)顯微鏡計數(shù)大于10個細(xì)胞的克隆數(shù)。3、細(xì)胞凋亡情況檢測: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AR的表達(dá)。5、Co-IP聯(lián)合Western bolt:檢測相關(guān)蛋白的表達(dá)。6、線粒體膜電位完整性檢測:采用羅丹明123染色法用流式細(xì)胞儀分析。7、活性氧檢測:采用10μM DCFH-DA對樣本進(jìn)行染色,隨后用流式細(xì)胞儀分析。8、實(shí)時熒光定量PCR:根據(jù)Takara試劑盒說明書操作,擴(kuò)增結(jié)束后得到各檢測基因的Cq值?9、裸鼠載體實(shí)驗(yàn):SPF級裸鼠右側(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:檢測腫瘤組織中的蛋白表達(dá)情況。實(shí)驗(yàn)結(jié)果1、b-AP15對前列腺癌細(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對前列腺癌細(xì)胞和正常細(xì)胞的抑制作用沒有明顯的細(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。通過羅丹明123染色法,流式細(xì)胞儀進(jìn)行檢測發(fā)現(xiàn)b-AP15能引起線粒體跨膜電位下降。對LNCa P和PC-3兩種細(xì)胞系進(jìn)行濃度和時間依賴處理,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,說明b-AP15是通過抑制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RT-PCR和免疫共沉淀實(shí)驗(yàn)檢測發(fā)現(xiàn)AR的抑制是通過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)果說明b-AP15對AR的抑制主要是通過抑制USP14發(fā)揮的作用。7、b-AP15對BALB/c裸鼠異種移植瘤的影響與對照組比較,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并對心,肝,腎功能沒有影響,說明b-AP15的毒性作用是可控的,對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 progress of some patients with deadly and incurable metastatic castration resistant prostate cancer (castrate-resistant prostate, cancer, CRPC), prostate cancer (Prostate Cancer PCa) is still a major cause of cancer-related deaths in men. The ubiquitin proteasome system (Ubiquitin-Proteasome, System, UPS) is fine Methods cell protein highly specific and selective degradation, and go through the dynamic balance between the ubiquitination of most proteins to control the fate of ubiquitin to substrate regulation. Recent studies show that deubiquitinating enzymes (Deubiquitinases, DUBs) has become a new target for cancer therapy, it can regulate a variety of cellular processes, including cell cycle control And in response to DNA damage and repair, apoptosis, chromatin modification and various signal transduction pathways. Boron for Zomi (bortezomib/Velcade) is the inhibitor of the 20S proteasome, has been approved by the FDA for treatment of multiple myeloma and lymphoma and other diseases and has good curative effect, confirmed by the ubiquitin proteasome system in cancer treatment a An important target, it also proves that the UPS component is an effective antitumor new molecular target, attracted a further study and exploration of the proteasome system, so as to seek more promising anticancer drugs. The androgen receptor (Androgen Receptor, AR) is closely related with the occurrence and development of prostate cancer it is a kind of. Androgen dependent transcription factor that belongs to the nuclear receptor superfamily. Usually can be observed in AR gene amplification and mutation in prostate cancer, the survival of AR signal pathway governs prostate cancer, proliferation and growth. We find that the deubiquitinating enzyme USP14 can stabilize and adjust the AR of the previous studies, inhibition of USP14 can promote AR ubiquitination degradation from The inhibition of AR dependent proliferation of prostate cancer cells, but had no effect on AR non dependent prostate cancer cells. A novel small molecule b-AP15 has been identified as 19S USP14/UC HL5 (DUBs) proteasome inhibitor, inhibition of proliferation and apoptosis can be induced by a variety of human tumor cell lines. In this study, we intend to further investigate and restrain USP14 And UCHL5 are synergistic and regulation effects on AR dependent and non dependent prostate cancer antitumor effect of AR. According to the results of our experiments showed that b-AP15 can promote the degradation of AR, but this effect is mainly through inhibition of USP14 function, and functional regulation of UCHL5 control has nothing to do, and found that b-AP15 inhibition induced by UPS, The activation of caspases, resulting in endoplasmic reticulum stress and oxidative stress caused by AR dependent and non dependent prostate cancer cell proliferation inhibition and apoptosis. Methods 1, cell viability was detected by MTS method and CCK-8 method to detect the effect of b-AP15 on prostate cancer and normal prostate epithelial cell viability.2, clone formation experiment: Clone Formation experiment Processing methods above. The number of clones with.3 optical microscope count greater than 10 cells, the cell apoptosis detected by Annexin V-FITC/Propidium iodide (PI) markers of cell death by apoptosis analysis and fluorescence microscopy and flow cytometry and photographed cell morphological changes of.4, Si RNA and UCHL5 USP14 transfection: knockout The expression of.5 AR, to detect the expression of.6 Co-IP protein combined with Western bolt:, the integrity of the mitochondrial membrane potential detection with flow cytometry analysis of.7 123 by Luo Danming staining, ROS detection: using 10 M DCFH-DA staining of samples, followed by flow cytometry analysis of.8, real-time fluorescence quantitative PCR: Takara Kit according to said The book, after the end of each gene amplification detection value of Cq? 9, the carrier in nude mice experiment: SPF grade right flank of nude mice inoculated subcutaneously with PC-3 cells, b-AP15 intraperitoneal injection, observe the mice weight and tumor volume changes of.10, immunohistochemistry, tumor tissue in the detection of protein expression. Results 1. B-AP15 on the proliferation of prostate cancer cells Effect of different concentration (0-5 M) with b-AP15 AR on prostate cancer cell line LNCa P, 22Rv1, AR on prostate cancer cells PC-3, DU145 and WPMY-1 in prostatic stromal cells 24,48,72 after h, there are different degrees of inhibition of proliferation, showed that the inhibitory effect of b-AP15 on prostate cancer cells and normal cells is not obvious cell selection Optional. In addition, the results show that the formation of colony formation.2 b-AP15 inhibited LNCa P and PC-3 cell colony, b-AP15 induced cell cycle arrest in different concentrations of b-AP15 (0,0.5,1,2 M) on LNCa P and PC-3 24h cells after cell cycle analysis. The results show that with the increase of b-AP15 concentration, cell cycle two cell lines have been stuck in G0/G1.Western blot showed that b-AP15 significantly decreased the cell cycle protein cyclin D1, CDK6, CDK4, C DK2 and p-Rb (G1 to S marker protein) expression, and the expression of tumor suppressor gene p27 inhibited the function of cyclin-CDK increased.3, b-AP15 induced caspase dependent apoptosis in LNCa P b-AP15 PC-3 and Annexin-V/PI positive cells Of a significant increase in the percentage of morphological changes of.Western blot results of apoptosis showed that two cell lines and the activation of Caspase-3, -8, -9 increased significantly, PARP cutting with.4, b-AP15 induced apoptosis and mitochondrial dysfunction related to apoptosis mainly through two ways of endogenous and exogenous and endogenous regulation. Way Also known as the mitochondrial pathway. By 123 Luo Danming staining detection showed that b-AP15 can lead to the mitochondrial membrane potential decreased by flow cytometry. LNCa P and PC-3 two cell lines were concentration and time dependent processing, the results showed that b-AP15 induced anti apoptosis protein (Bcl-2) of the expression, and pro apoptotic protein (Bim, Bax, Noxa) significantly Increased. In addition, with the change of membrane permeability, the release of Pro apoptotic factors to the cytoplasm (cytochrome C) and apoptosis inducing factor (AIF) levels were also significantly increased.5, b-AP15 treatment can induce the production of ROS, antioxidant N- acetylcysteine (NAC) on apoptosis of.6 induced by b-AP15 reversal, b-AP15 inhibited LNCa P and PC-3 cells of eggs White body enzyme function and androgen receptor (AR) expression, resulting in endoplasmic reticulum stress. Low concentration of b-AP15 can cause the ubiquitinated protein (Ub-prs) aggregation, inhibition of proteasome function in early apoptosis, indicating that b-AP15 is the induction of apoptosis by inhibiting the function of UPS. It was found that b-AP15 could produce endoplasmic reticulum stress and inhibition of male Hormone receptor (AR) expression assays showed the inhibition of AR through ubiquitin mediated degradation rather than gene transcription by RT-PCR and immunoprecipitation. In addition, with the UCHL5 Si RNA P was transfected into LNCa cells, the expression of Western blot detected by AR, results showed that knockdown of UCHL5 did not inhibit AR, combined with the preliminary experimental results b-AP15 of AR suppression The main business is the role of.7 by inhibiting USP14 play, compared the effect of b-AP15 on BALB/c xenografts in nude mice and the control, the results showed that b-AP15 treatment group, the tumor volume and tumor weight decreased significantly, no significant difference between the two groups of nude mice. The tumor weight of immunohistochemical staining after the b-AP15 treatment, proteasome pan In the substrate protein aggregation, activation of p27 and increase the expression of Caspase-3. Two groups were detected in nude mice myocardium, liver and kidney tissues of creatine kinase, alanine aminotransferase and creatinine index, the results show that the b-AP15 and the heart, liver, kidney function has no effect, that the toxicity effect of b-AP15 is controllable, and has broad the treatment of prostate cancer Future. Conclusion 1 b-AP15 can induce in vivo androgen receptor dependent and non prostate cancer cell apoptosis.
【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.25

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