PLK1抑制剂BI2536对前列腺癌的抑制作用研究

发布时间：2018-06-21 02:39

本文选题：PLK1 + BI2536　；参考：《中国农业大学》2015年博士论文

【摘要】：前列腺癌是全世界男性恶性肿瘤发病率中居第二位的癌症。雄激素受体(AR)在前列腺癌细胞增殖过程中起关键作用,AR信号通路被雄激素激活是前列腺癌生长所必需的,因此阻断雄激素产生的去势疗法是前列腺癌治疗的常用手段,包括手术去势和抗雄激素药物的使用。然而去势疗法的时效有限,前列腺癌会逐渐发展成为去势抵抗性前列腺癌(CRPC)。CRPC的生长不再受去势治疗的影响,病情难以控制,患者存活期较短。前列腺癌向CRPC发展的过程中,关键点在于重新激活因去势而被抑制的AR信号通路。之前的研究发现,AR信号通路的激活依赖于以下几个因素：①AR的变异,包括基因拷贝数增加造成的高表达、点突变造成的配体分子识别能力下降、隐蔽性外显子造成的剪接变异体。②与其它信号通路如PI3K-AKT-mTOR的互作。③前列腺癌细胞自身合成雄激素并激活AR信号通路。另外,Polo样激酶1(PLK1)在进入CRPC阶段之后表达量升高。PLK1是参与细胞有丝分裂的重要激酶,能间接激活PI3K-AKT-mTOR信号通路,其在癌细胞内的表达量与细胞增殖速度正相关。本课题的研究目的在于寻找PLK1与AR信号通路之间的关系。去势疗法造成前列腺癌细胞缺乏雄激素并导致氧化应激的产生。氧化应激促进了前列腺癌向CRPC的发展。我们首先研究了氧化应激对前列腺癌细胞的影响,发现氧化应激能够激活转录因子NF-κB从而启动PLK1的表达,能够激活PI3K-AKT-mTOR1信号通路,能够促进AR的表达。本研究对这三者之间的关系进行了初步探索,认为氧化应激条件下PI3K-AKT-mTOR信号通路很可能受PLK1影响,而且对AR的过表达起决定作用。通过进一步研究非氧化应激条件下PLK1与AR间的关系,发现PLK1通过激活PI3K-AKT-mTOR信号通路来激活转录因子TWIST1并启动AR基因的转录。PLK1抑制剂BI2536对于AR的活性和表达量都有抑制作用。BI2536还能通过抑制SREBP来抑制前列腺癌细胞内的脂代谢和雄激素合成,从另一个方面抑制AR信号通路。对PLK1和AR信号通路的进一步研究表明,AR信号通路的激活会导致PLK1表达量上升,PLK1与AR信号通路之间存在相互促进的关系。将PLK1抑制剂BI2536与目前广泛使用的CRPC治疗药物MDV3100或abiraterone联合使用,在细胞实验中能够更有效的抑制AR信号通路。BI2536与MDV3100联合使用,能够解除前列腺癌细胞MR49F的MDV3100抗性。BI2536与abiraterone联合使用,在LuCaP35CR异种移植瘤实验中对肿瘤生长的抑制效果优于单独给药。本研究阐明了前列腺癌细胞中PLK1对AR信号通路正调控作用的分子机制,将促进对前列腺癌细胞信号通路与癌症发展的进一步理解。同时本研究尝试将BI2536与现有药物联合使用进行抗癌实验,为前列腺癌的新治疗方案提供一种可能性。
[Abstract]:Prostate cancer is the second most common cancer in the world. Androgen receptor (ARN) plays a key role in the proliferation of prostate cancer cells. The activation of AR signal pathway by androgen is necessary for prostate cancer growth, so blocking androgen castration is a common method in prostate cancer treatment. These include surgical castration and the use of androgen drugs. However, the time of castration therapy is limited, prostate cancer will gradually develop into castrated resistant prostate cancer, the growth of CRPC.CRPC is no longer affected by castration therapy, the condition is difficult to control, and the survival period of patients is short. The key to the progression of prostate cancer to CRPC is to reactivate the AR signaling pathway suppressed by castration. Previous studies have found that activation of the AR signaling pathway depends on variation in the following factors: 1 / 1AR, including high expression due to increased copy number of genes, and reduced recognition ability of ligand due to point mutation. Interaction of splicing variant .2 caused by hidden exon with other signal pathways such as PI3K-AKT-mTOR. 3 Prostate cancer cells self-synthesize androgen and activate AR signaling pathway. In addition, PI3K-AKT-mTOR signaling pathway can be indirectly activated by PI3K-AKT-mTOR signal pathway. The expression of PI3K-AKT-mTOR in cancer cells is positively correlated with the expression of PLK1. The purpose of this study is to find out the relationship between PLK1 and AR signal pathway. Castration results in a lack of androgen and oxidative stress in prostate cancer cells. Oxidative stress promotes the progression of prostate cancer to CRPC. We first studied the effect of oxidative stress on prostate cancer cells. It was found that oxidative stress could activate the expression of transcription factor NF- 魏 B, activate the expression of PLK1, activate the PI3K-AKT-mTOR1 signaling pathway and promote the expression of AR. This study explored the relationship between these three factors and suggested that the PI3K-AKT-mTOR signaling pathway may be affected by PLK1 under oxidative stress and play a decisive role in the overexpression of AR. To further study the relationship between PLK1 and AR under non-oxidative stress, We found that PLK1 activates transcription factor TWIST1 by activating PI3K-AKT-mTOR signaling pathway and activates transcription of AR gene. PLK1 inhibitor BI2536 can inhibit AR activity and expression. BI2536 can also inhibit lipid in prostate cancer cells by inhibiting SREBP. Metabolism and androgen synthesis, The AR signaling pathway was inhibited in another way. Further studies on the PLK1 and AR signaling pathways show that the activation of the AR signaling pathway leads to a mutually reinforcing relationship between PLK1 expression and AR signaling pathway. The combination of PLK1 inhibitor BI2536 and MDV3100 or abiraterone, which is widely used in prostate cancer cell line, can effectively inhibit AR signaling pathway. BI2536 and MDV3100 can release MDV3100 resistance of prostate cancer cell line MR49F. BI2536 can be used in combination with abiraterone. The inhibitory effect of LuCaP 35 CR on tumor growth was superior to that of single drug administration in xenotransplantation of LuCaP 35 CR. In this study, the molecular mechanism of the positive regulation of the AR signaling pathway by PLK1 in prostate cancer cells was elucidated, which will promote the further understanding of the signal pathway and the development of cancer in prostate cancer cells. At the same time, we try to use BI2536 in combination with existing drugs to carry out anticancer experiments, which provides a possibility for a new treatment of prostate cancer.
【学位授予单位】：中国农业大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R737.25

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