本文選題：腫瘤代謝 + 腺苷酸激活蛋白激酶��； 參考：《天津醫(yī)科大學(xué)》2016年博士論文

【摘要】：背景腺苷酸激活蛋白激酶(AMP-activated protein kinase,AMPK)與乙酰輔酶A羧化酶(Acetyl-Co A Carboxylase,ACC)作為其各自代謝調(diào)節(jié)過程中的關(guān)鍵環(huán)節(jié),相互之間存在密切聯(lián)系,形成細(xì)胞內(nèi)的上游和下游的信號(hào)通路。AMPK是機(jī)體和細(xì)胞能量代謝的調(diào)節(jié)器,當(dāng)細(xì)胞內(nèi)ATP水平下降時(shí),細(xì)胞處于能量應(yīng)激狀態(tài)下,AMPK激活,為細(xì)胞提供能量[1]。ACC是存在于胞漿中含有生物素的變構(gòu)羧化酶,是脂肪酸代謝過程中的限速酶,其使乙酰輔酶A羧化成丙二酰輔酶A。在人類ACC有兩種亞型,ACC1和ACC2。近年來發(fā)現(xiàn)腫瘤代謝在腫瘤的發(fā)生、侵襲、轉(zhuǎn)移和耐藥過程中起著重要的作用[2],而AMPK和ACC在腫瘤代謝中發(fā)揮著核心作用。在我們的前期研究中發(fā)現(xiàn),一種表皮生長(zhǎng)因子受體阻斷抗體,西妥昔單抗可以抑制腫瘤代謝并且可以在腫瘤細(xì)胞中逆轉(zhuǎn)Warburg效應(yīng)(腫瘤有氧糖酵解)[3]。我們同樣發(fā)現(xiàn)AMPK的短暫激活在應(yīng)用西妥昔單抗治療腫瘤細(xì)胞的早期是一項(xiàng)重要指標(biāo),但長(zhǎng)期且持續(xù)激活的AMPK水平是腫瘤耐藥的一種機(jī)制[4]。與西妥昔單抗治療前的頭頸鱗癌比較,治療后組織及細(xì)胞高表達(dá)磷酸化AMPK、磷酸化ACC及ACC。我們?cè)O(shè)計(jì)本實(shí)驗(yàn),進(jìn)一步明確ACC在頭頸鱗癌組織及細(xì)胞中的表達(dá)方式;從臨床水平、細(xì)胞水平及動(dòng)物實(shí)驗(yàn)水平探索ACC在腫瘤代謝過程中功能及其分子調(diào)控機(jī)制。方法1.應(yīng)用分子克隆方法構(gòu)建乏氧誘導(dǎo)因子-1α(Hypoxia inducible factor-1α,HIF-1α)與乙酰輔酶A羧化酶(Acetyl-Co A Carboxylase,ACC)過表達(dá)質(zhì)粒,構(gòu)建慢病毒穩(wěn)定轉(zhuǎn)染系統(tǒng),建立穩(wěn)定過表達(dá)HIF-1α的HEK293_HIF-1α細(xì)胞系;用Western blot,葡萄糖消耗實(shí)驗(yàn)(Glucose consumption assay)檢測(cè)所構(gòu)建穩(wěn)系HEK293_HIF-1α的表達(dá)水平及其對(duì)于葡萄糖的消耗水平。2.應(yīng)用分子克隆方法構(gòu)建乙酰輔酶A羧化酶(Acetyl-Co A Carboxylase,ACC),ACC1_S79A及ACC2_S212A過表達(dá)質(zhì)粒,構(gòu)建慢病毒穩(wěn)定轉(zhuǎn)染系統(tǒng),建立穩(wěn)定過表達(dá)的ACC1_S79A和ACC2_S212A的HEK293_HIF-1α細(xì)胞系;用Western blot,細(xì)胞生存死亡實(shí)驗(yàn)(Live/dead cell viability assay)檢測(cè)AMPK、ACC及其磷酸化蛋白的表達(dá)水平,檢測(cè)在能量應(yīng)激狀況下(低糖)不同穩(wěn)轉(zhuǎn)細(xì)胞的存活率。3.應(yīng)用Western blot、MTT檢測(cè)不同頭頸鱗癌細(xì)胞系代謝相關(guān)指標(biāo)及對(duì)西妥昔單抗敏感性。應(yīng)用RT-RCR檢測(cè)不同細(xì)胞系A(chǔ)CC1和ACC2m RNA水平。應(yīng)用放線菌酮(Cycloheximide,CHX)抑制蛋白合成,檢測(cè)ACC降解水平。4.應(yīng)用ACC1_S79A及ACC2_S212A過表達(dá)質(zhì)粒及ACC1、ACC2小干擾RNA(si RNA)轉(zhuǎn)染頭頸鱗癌細(xì)胞系;用Western blot、細(xì)胞生存死亡實(shí)驗(yàn)(Live/dead cell viability assay)、細(xì)胞增殖實(shí)驗(yàn)(Cell proliferation assay)、凋亡實(shí)驗(yàn)(Apoptosis assay)檢測(cè)腫瘤細(xì)胞經(jīng)過西妥昔單抗治療前后AMPK、ACC及其磷酸化蛋白的表達(dá)水平及細(xì)胞存活率,細(xì)胞凋亡狀況。5.應(yīng)用ACC及脂肪酸合成抑制劑5-十四烷氧基-2-呋喃甲酸(5-Tetradecyloxy-2-furoic acid,TOFA)抑制ACC,通過Western blot、流式細(xì)胞技術(shù)、細(xì)胞增殖實(shí)驗(yàn)(MTT)、凋亡實(shí)驗(yàn)(Apoptosis assay)檢測(cè)TOFA對(duì)西妥昔單抗耐藥頭頸鱗癌細(xì)胞系的作用。6.構(gòu)建裸鼠(Nude Mouse)皮下移植瘤模型,應(yīng)用TOFA,檢測(cè)腫瘤的增殖情況,并通過熒光成像(Luciferase image)和免疫組織化學(xué)的方法,探討磷酸化AMPK、磷酸化ACC及ACC的表達(dá)與西妥昔單抗治療的相關(guān)性。7.搜集頭頸鱗癌組織石蠟標(biāo)本資料進(jìn)行回顧性研究,AMPK-T172p,ACC-S79p和ACC的表達(dá)表達(dá)水平與西妥昔單抗治療的相關(guān)性。結(jié)果1.轉(zhuǎn)染HIF-1α使HEK293細(xì)胞腫瘤化特征。予以正常胚胎腎細(xì)胞HEK293細(xì)胞系過表達(dá)HIF-1α_P402A/P564A和HIF-1α_(35)ODD后,發(fā)現(xiàn)轉(zhuǎn)染HIF-1α的HEK293細(xì)胞對(duì)于葡萄糖的消耗明顯增加(由于Warberg效應(yīng)),同時(shí)伴隨AMPK的激活(表現(xiàn)為AMPK T172磷酸化的增加)和ACC的抑制(表現(xiàn)為ACC S79磷酸化的增加)。轉(zhuǎn)染HIF-1α的HEK293細(xì)胞對(duì)于低糖環(huán)境更敏感。2.能量應(yīng)激(低糖)狀況下ACC表現(xiàn)出對(duì)細(xì)胞重要的保護(hù)功能。過表達(dá)的ACC1_S79A和ACC2_S212A對(duì)于AMPK的激活沒有作用,對(duì)于低糖所導(dǎo)致的內(nèi)源性的ACC的抑制沒有作用,這表明ACC可以保護(hù)低糖環(huán)境中的細(xì)胞存活是不由AMPK的激活所介導(dǎo)的。而且,敲除內(nèi)源性ACC1和ACC2,特別是ACC1導(dǎo)致了在低糖環(huán)境下更多的HEK293和HEK293 HIF-1α_P402A/P564A細(xì)胞的死亡。在HEK293 HIF-1α_P402A/P564A細(xì)胞中敲除ACC1,16小時(shí)后約80%細(xì)胞死亡。3.磷酸化AMPK和磷酸化ACC的表達(dá)水平與頭頸鱗癌細(xì)胞對(duì)西妥昔單抗的耐藥相關(guān)。我們的前期研究發(fā)現(xiàn)西妥昔單抗可通過下調(diào)HIF-1α和抑制HIF-1α調(diào)節(jié)的糖酵解來激活A(yù)MPK并且抑制HNSCC細(xì)胞的增殖。進(jìn)一步發(fā)現(xiàn)高表達(dá)的磷酸化AMPK T172和磷酸化ACC S79與頭頸鱗癌細(xì)胞系對(duì)西妥昔單抗的敏感性呈負(fù)相關(guān)。這個(gè)結(jié)果同樣在獲得性耐藥西妥昔單抗的兩對(duì)等基因細(xì)胞中HN5/HN5-R和Fa Du/Fa Du-R中得到證實(shí)。進(jìn)一步發(fā)現(xiàn)穩(wěn)轉(zhuǎn)HN5HIF-1α_P402A/P564A細(xì)胞激活A(yù)MPK抑制ACC,對(duì)西妥昔單抗耐藥。4.ACC的表達(dá)水平與西妥昔單抗耐藥相關(guān)。RT-PCR的結(jié)果顯示增加的ACC不是由于轉(zhuǎn)錄水平的增加引起的,經(jīng)過西妥昔單抗治療后,HN5細(xì)胞中SREBP-1c下降明顯,而HN5-R細(xì)胞中SREBP-1c無明顯變化,相似的結(jié)果在另外兩種耐藥細(xì)胞UMSCC1和MDA1986中得到證實(shí)。ACC在HN5-R中明顯比在HN5中更加穩(wěn)定,代謝減慢,預(yù)示著一種轉(zhuǎn)錄后機(jī)制是ACC升高的原因。應(yīng)用si RNA技術(shù)在HN5中敲除內(nèi)源性ACC1和ACC2并沒有影響西妥昔單抗治療后凋亡的水平,而在兩種耐藥細(xì)胞HN5-R和UMSCC1中,可以看到明顯的凋亡增加。5.西妥昔單抗耐藥細(xì)胞對(duì)于TOFA更敏感,包括獲得性耐藥的HN5-R,天然耐藥的UMSCC1和MDA1986。而且長(zhǎng)期慢性暴露于TOFA治療的UMSCC1-TOFA耐藥細(xì)胞逆轉(zhuǎn)為對(duì)西妥昔單抗敏感。TOFA與西妥昔單抗和用能明顯的引起耐藥細(xì)胞HN5-R、UMSCC1和MDA1986的凋亡,聯(lián)合用藥效果明顯。6.體內(nèi)動(dòng)物實(shí)驗(yàn)證實(shí)聯(lián)合用藥對(duì)于西妥昔單抗耐藥細(xì)胞有明顯的效果。我們通過測(cè)量腫瘤的大小和IVIS腫瘤成像測(cè)量。應(yīng)用TOFA治療沒有使裸鼠體重下降。免疫組化證實(shí)經(jīng)西妥昔單抗治療腫瘤組織磷酸化AMPK T172、磷酸化ACC S79和ACC與對(duì)照未治療組增加,聯(lián)合用藥組免疫組化結(jié)果與體外細(xì)胞實(shí)驗(yàn)相符,應(yīng)用UMSCC1細(xì)胞同樣得到證實(shí)。7.我們收集了18例頭頸鱗癌患者,其中6例經(jīng)過化療+西妥昔單抗治療后手術(shù),剩余18例為對(duì)照化療后手術(shù)。其中第六例患者為化療后手術(shù),復(fù)發(fā)后給予化療+西妥昔單抗治療后再次手術(shù)。以第六例患者為例,可以明顯發(fā)現(xiàn)經(jīng)過西妥昔單抗治療后,磷酸化AMPK T172、磷酸化ACC S79和ACC全部高表達(dá)。結(jié)論1.腫瘤處于應(yīng)激狀態(tài)下,ACC發(fā)揮著不可或缺的雙重作用使腫瘤細(xì)胞得以存活、生長(zhǎng)和增殖。2.ACC在腫瘤細(xì)胞由依賴于糖酵解轉(zhuǎn)化為依賴于脂肪酸氧化的腫瘤代謝重新調(diào)整過程中發(fā)揮重要作用。3.對(duì)于西妥昔單抗耐藥腫瘤,以抗ACC為靶點(diǎn),我們可以發(fā)現(xiàn)合理的治療手段,也可能增加其他以抗腫瘤Warberg效應(yīng)為靶點(diǎn)的治療效果。
[Abstract]:Background adenylate activated protein kinase (AMP-activated protein kinase, AMPK) and acetyl coenzyme A carboxylase (Acetyl-Co A Carboxylase, ACC) are the key links in their respective metabolic regulation processes. There is a close relationship between each other, and the formation of signal pathways in the upstream and downstream of the cell is the regulation of the body and cell energy metabolism. When the ATP level in the cell falls, the cell is in the state of energy stress, AMPK activates, and the energy [1].ACC is an allosteric carboxytransferase containing biotin in the cytoplasm. It is a speed limiting enzyme in the metabolic process of fatty acid. It makes acetyl coenzyme A carboxylation to propane two acyl coenzyme A. in two subtypes of human ACC, ACC1 and ACC2. in recent years. It is found that tumor metabolism plays an important role in the process of tumor occurrence, invasion, metastasis and drug resistance, and AMPK and ACC play a core role in tumor metabolism. In our previous study, a kind of epidermal growth factor receptor blocking antibody, cetuximab can inhibit tumor metabolism and can reverse W in tumor cells. The Arburg effect (tumor aerobic glycolysis) [3]. we also found that the transient activation of AMPK is an important indicator in the early use of cetuximab in the treatment of tumor cells, but the long-term and continuously activated AMPK level is a mechanism of tumor resistance, [4]. and cetuximab before the treatment of head and neck squamous cell carcinoma, after treatment, tissue and cell high surface AMPK, phosphorylated ACC and ACC., we designed this experiment to further clarify the expression of ACC in the tissues and cells of head and neck squamous cell carcinoma, and explore the function of ACC in the process of tumor metabolism and its molecular regulation mechanism from clinical level, cell level and animal experimental level. Method 1. the use of molecular cloning method to construct hypoxia inducible factor -1 alpha. Hypoxia inducible factor-1 alpha, HIF-1 alpha) and acetyl coenzyme A carboxylase (Acetyl-Co A Carboxylase, ACC) overexpressed plasmids, constructed the lentivirus stable transfection system, and established a HEK293_HIF-1 alpha cell line for stable overexpression of HIF-1 a. Expression level and glucose consumption level.2. application molecular cloning method to construct acetyl coenzyme A carboxylase (Acetyl-Co A Carboxylase, ACC), ACC1_S79A and ACC2_S212A overexpressed plasmids, construct lentivirus stable transfection system, establish a stable overexpressed ACC1_S79A and ACC2_S212A HEK293_HIF-1 alpha cell line. Cell survival and death test (Live/dead cell viability assay) test the expression level of AMPK, ACC and phosphorylated protein, detect the survival rate of different stable cells under energy stress (low sugar).3. application Western blot, MTT detection of different head and neck squamous cell carcinoma cell lines for Xie Xiang index and sensitivity to cetuximab. Use RT-RCR detection ACC1 and ACC2m RNA levels in different cell lines. Using Cycloheximide (CHX) inhibition protein synthesis, ACC degradation level.4. application ACC1_S79A and ACC2_S212A overexpressed plasmids and ACC1, ACC2 small interference RNA to transfect the head and neck squamous cell carcinoma cell lines. The cell proliferation test (Cell proliferation assay), apoptosis experiment (Apoptosis assay) was used to detect the expression level of AMPK, ACC and phosphorylated protein and cell survival rate before and after treatment with cetuximab, and the apoptosis status.5. applied ACC and fatty acid synthesis inhibitor 5- fourteen alkoxy -2- furanoic acid (5-Tetradecyloxy-2-furoic) (5-Tetradecyloxy-2-furoic) Acid, TOFA) inhibition of ACC, through Western blot, flow cytometry, cell proliferation test (MTT), apoptosis experiment (Apoptosis assay) detection of the effect of TOFA on cimiximab resistant head and neck squamous cell carcinoma cell line,.6. to construct nude mice (Nude Mouse) subcutaneous transplantation tumor model. Age) and immunohistochemical method, the relationship between the expression of phosphorylated AMPK, phosphorylated ACC and ACC and the treatment of cetuximab,.7. collection of paraffin specimens from the squamous cell carcinoma of the head and neck, the correlation between the expression level of AMPK-T172p, ACC-S79p and ACC and the correlativity of cetuximab treatment. Results 1. transfection of HIF-1 alpha to HEK293 The characteristics of cell oncology. After the expression of HIF-1 alpha _P402A/P564A and HIF-1 alpha (35) ODD in the normal embryonic renal cell line, it was found that the consumption of HEK293 cells transfected with HIF-1 a was significantly increased (due to Warberg effect), accompanied by the activation of AMPK (the increase of AMPK T172 phosphorylation) and the inhibition of ACC. The increase of 79 phosphorylation. HEK293 cells transfected with HIF-1 a are more sensitive to.2. energy stress (low sugar) in the low sugar environment. ACC shows an important protective function to the cells. The overexpressed ACC1_S79A and ACC2_S212A have no effect on the activation of AMPK, and the inhibition of the inhibition of endogenous ACC caused by low sugar shows that ACC can be found. The survival of cells in the protected low sugar environment was not mediated by the activation of AMPK. Moreover, the knockout of endogenous ACC1 and ACC2, especially ACC1, resulted in more HEK293 and HEK293 HIF-1 alpha _P402A/P564A cells in the low sugar environment. About 80% cell deaths in HEK293 HIF-1 alpha _P402A/P564A cells were phosphorylated. And the expression level of phosphorylated ACC is associated with the resistance of the head and neck squamous cell carcinoma cells to cetuximab. Our previous study found that cetuximab can activate AMPK and inhibit the proliferation of HNSCC cells by lowering the glycolysis of HIF-1 A and inhibiting HIF-1 a. The high expression of phosphorylated AMPK T172 and phosphorylated ACC S79 and head are also found. The sensitivity of cervical squamous cell carcinoma cell line to cetuximab is negatively correlated. This result is also confirmed in HN5/HN5-R and Fa Du/Fa Du-R in the two peer-to-peer gene cells of acquired resistant cetuximab. It is further found that stable HN5HIF-1 alpha _P402A/P564A cells activate AMPK to inhibit ACC and the expression level of resistant.4.ACC to cetuximab. The results of cetuximab resistance related.RT-PCR showed that the increase of ACC was not caused by the increase of transcriptional level. After cetuximab treatment, SREBP-1c decreased significantly in HN5 cells, while SREBP-1c in HN5-R cells did not change significantly. The similar results were confirmed in the other two resistant cells, UMSCC1 and MDA1986, in HN5-R. It is obviously more stable and slower than in HN5, indicating that a post transcriptional mechanism is the cause of the increase of ACC. The use of Si RNA technique to knock out endogenous ACC1 and ACC2 in HN5 does not affect the level of apoptosis after cetuximab, and a significant increase in apoptosis in two resistant cells, HN5-R and UMSCC1, can be seen in.5. cetuximab. Drug-resistant cells are more sensitive to TOFA, including acquired resistance to HN5-R, naturally resistant UMSCC1 and MDA1986., and the long-term chronic exposure to TOFA for UMSCC1-TOFA resistant cells reverses the apoptosis of the sensitive.TOFA and cetuximab against cetuximab and the drug resistant cells HN5-R, UMSCC1 and MDA1986, combined with the effect of drug use. .6. in vivo animal experiments confirmed that the combined use of combined drugs has a significant effect on cetuximab resistant cells. We measured tumor size and IVIS tumor imaging. TOFA treatment did not reduce the weight loss of nude mice. Immunohistochemistry proved that cetuximab was used to treat tumor tissue phosphorylated AMPK T172, phosphorylated ACC S79 and ACC. Compared with the untreated group, the results of the immunization of the combined drug group were consistent with the in vitro cell test. The UMSCC1 cells were also confirmed by the UMSCC1 cells. We collected 6 cases of head and neck squamous cell carcinoma, of which 6 cases were treated after chemotherapy plus cetuximab, and the remaining 18 cases were treated after chemotherapy. Of these, sixth patients underwent postoperative chemotherapy surgery. After treatment with chemotherapy plus cetuximab, reoperation was performed after treatment. In sixth patients, it was found that after cetuximab treatment, phosphorylated AMPK T172, phosphorylated ACC S79 and ACC were all highly expressed. Conclusion the 1. tumor is in stress state, and ACC plays an indispensable double role in the survival, growth and growth of the tumor cells. Proliferating.2.ACC plays an important role in the process of tumor metabolism dependent on glycolysis to tumor metabolism dependent on fatty acid oxidation..3. is a target for resistant to cetuximab resistant tumor, with anti ACC as a target. We can find a reasonable therapeutic method and may also increase the therapeutic effect of his target on the anti tumor Warberg effect. Fruit.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R730.2

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