本文選題：齊墩果酸 + 海兔素　； 參考：《中國科學院研究生院（海洋研究所）》2014年博士論文

【摘要】：本文研究了兩種天然產(chǎn)物的抗腫瘤作用。首先研究了齊墩果酸的抗腫瘤作用。齊墩果酸具有廣泛的生物活性，我們前期的研究表明，齊墩果酸可以通過促進細胞凋亡誘導腫瘤細胞凋亡，但其作用的分子靶點尚不清楚。近幾年人們對腫瘤的發(fā)生機制有了新的認識，有氧糖酵解是腫瘤細胞的一大特點（又稱為Warburg效應），對于腫瘤細胞的快速增殖非常重要。M型丙酮酸激酶的2型剪切體（PKM2）是誘導和維持有氧糖酵解的關(guān)鍵代謝酶，而且越來越多的證據(jù)表明PKM2是一個潛在的腫瘤治療靶點。本研究利用多種腫瘤細胞系，檢測齊墩果酸對腫瘤細胞代謝的影響。結(jié)果顯示齊墩果酸能夠抑制腫瘤細胞的有氧糖酵解（葡萄糖吸收率下降29.1%-30%，乳酸產(chǎn)量下降16.2%-28.3%，氧氣消耗率上升17.8%-54.5%）。代謝關(guān)鍵酶PKM在齊墩果酸的作用下由2型剪切體向1型轉(zhuǎn)變。進一步的研究又發(fā)現(xiàn)，齊墩果酸對腫瘤代謝的影響是通過對mTOR/c-Myc/hnRNPA1/hnPNPA2/PKM通路的作用實現(xiàn)。 本文還對海洋天然產(chǎn)物海兔素與TRAIL協(xié)同抑制腫瘤生長的分子機制進行了研究。通過多株腫瘤細胞系得到的實驗數(shù)據(jù)表明，海兔素能夠通過對p38MAPK/survivin通路的影響提高TRAIL對腫瘤細胞的殺傷能力（提升2.58-6.15倍）。 綜上所述，，本研究證明齊墩果酸可以通過減少PKM2的表達量抑制腫瘤的有氧糖酵解，肯定了PKM2是一個有效的腫瘤治療靶點；海兔素能夠增強腫瘤耐藥細胞對TRAIL的敏感性。
[Abstract]:The anti-tumor effects of two natural products were studied in this paper. Firstly, the anti-tumor effect of oleanolic acid was studied. Oleanolic acid has a wide range of biological activities. Our previous studies have shown that oleanolic acid can induce apoptosis of tumor cells by promoting apoptosis, but the molecular target of its action is not clear. In recent years, people have a new understanding of the mechanism of tumor development. Aerobic glycolysis is a major characteristic of tumor cells (also called Warburg effect). It is very important for the rapid proliferation of tumor cells. Type 2 shearing body (PKM2) of pyruvate kinase (PKM2) is the key metabolic enzyme to induce and maintain aerobic glycolysis. And there is growing evidence that PKM2 is a potential tumor therapy target. In this study, the effects of oleanolic acid on the metabolism of tumor cells were detected by using a variety of tumor cell lines. The results showed that oleanolic acid could inhibit aerobic glycolysis of tumor cells (glucose absorption decreased 29.1-30, lactate production decreased 16.2-28.3and oxygen consumption rate increased 17.8- 54.5%). The metabolic key enzyme PKM changed from type 2 shearing body to type 1 under the action of oleanolic acid. Further studies showed that the effect of oleanolic acid on tumor metabolism was mediated by the role of mTOR / c-Myc / hnRNPA1 / hnPNPA2 / PKM pathway. The molecular mechanism of the synergistic inhibition of trail and trail on tumor growth was also studied. The experimental data obtained from a number of tumor cell lines showed that the ability of trail to kill tumor cells was increased by 2.58-6.15 times through the effect of p38 MAPK / survivin pathway. In conclusion, this study demonstrated that oleanolic acid could inhibit aerobic glycolysis by reducing the expression of PKM2, which confirmed that PKM2 was an effective target for tumor therapy, and that capillarin could enhance the sensitivity of tumor resistant cells to trail.
【學位授予單位】：中國科學院研究生院（海洋研究所）
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R96

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