两种天然产物抗肿瘤作用的分子机制

发布时间：2018-06-26 04:10

本文选题：齐墩果酸 + 海兔素　；参考：《中国科学院研究生院（海洋研究所）》2014年博士论文

【摘要】：本文研究了两种天然产物的抗肿瘤作用。首先研究了齐墩果酸的抗肿瘤作用。齐墩果酸具有广泛的生物活性，我们前期的研究表明，齐墩果酸可以通过促进细胞凋亡诱导肿瘤细胞凋亡，但其作用的分子靶点尚不清楚。近几年人们对肿瘤的发生机制有了新的认识，有氧糖酵解是肿瘤细胞的一大特点（又称为Warburg效应），对于肿瘤细胞的快速增殖非常重要。M型丙酮酸激酶的2型剪切体（PKM2）是诱导和维持有氧糖酵解的关键代谢酶，而且越来越多的证据表明PKM2是一个潜在的肿瘤治疗靶点。本研究利用多种肿瘤细胞系，检测齐墩果酸对肿瘤细胞代谢的影响。结果显示齐墩果酸能够抑制肿瘤细胞的有氧糖酵解（葡萄糖吸收率下降29.1%-30%，乳酸产量下降16.2%-28.3%，氧气消耗率上升17.8%-54.5%）。代谢关键酶PKM在齐墩果酸的作用下由2型剪切体向1型转变。进一步的研究又发现，齐墩果酸对肿瘤代谢的影响是通过对mTOR/c-Myc/hnRNPA1/hnPNPA2/PKM通路的作用实现。本文还对海洋天然产物海兔素与TRAIL协同抑制肿瘤生长的分子机制进行了研究。通过多株肿瘤细胞系得到的实验数据表明，海兔素能够通过对p38MAPK/survivin通路的影响提高TRAIL对肿瘤细胞的杀伤能力（提升2.58-6.15倍）。综上所述，，本研究证明齐墩果酸可以通过减少PKM2的表达量抑制肿瘤的有氧糖酵解，肯定了PKM2是一个有效的肿瘤治疗靶点；海兔素能够增强肿瘤耐药细胞对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.
【学位授予单位】：中国科学院研究生院（海洋研究所）
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R96

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