JQ1与ABT-263协同治疗N-Myc扩增的小细胞肺癌的研究
发布时间：2018-10-18 08:50
【摘要】：小细胞肺癌是一种预后极差的恶性肿瘤。抗凋亡蛋白Bcl-2的过表达经常在小细胞肺癌中发生,这使其成为潜在的治疗靶点。以前的研究表明,靶向Bcl-2的抑制剂ABT-263对小细胞肺癌的抑制作用有限。在本研究中,我们首次发现共抑制N-Myc和Bcl-2在MYCN扩增的小细胞肺癌中具有很强的协同抗肿瘤作用。我们发现BET抑制剂JQ1能抑制MYCN扩增的小细胞肺癌N-Myc蛋白的表达。JQ1对N-Myc的抑制作用诱导MYCN扩增的小细胞肺癌凋亡蛋白Bim的表达。此外,JQ1诱导Bim上调使MYCN扩增的小细胞肺癌对ABT-263更加敏感,同时我们通过siRNA敲低Bim的实验证明了 JQ1/ABT-263的协同抑制是通过Bim蛋白上调发挥的。在MYCN扩增的小细胞肺癌中,JQ1/ABT-263共同处理可以显著降低Bim/Bcl-2的相互作用并抑制Bim与Mcl-1的相互作用。重要的是,JQ1/ABT-263可以协同抑制MYCN扩增的小细胞肺癌异种移植模型中肿瘤的生长。我们的研究表明JQ1/ABT-263是一种新型针对MYCN扩增小细胞肺癌的有效靶向治疗策略。
[Abstract]:Small cell lung cancer is a malignant tumor with poor prognosis. Overexpression of anti-apoptotic protein Bcl-2 often occurs in small cell lung cancer, which makes it a potential therapeutic target. Previous studies have shown that ABT-263, an inhibitor of Bcl-2, has limited inhibitory effects on small cell lung cancer. In this study, we found for the first time that co-inhibition of N-Myc and Bcl-2 had strong synergistic antitumor effects in MYCN amplified small cell lung cancer. We found that JQ1, a BET inhibitor, could inhibit the expression of N-Myc protein in small cell lung cancer amplified by MYCN, and the inhibitory effect of JQ1 on N-Myc induced the expression of Bim protein in MYCN amplified small cell lung cancer. In addition, the up-regulation of Bim induced by JQ1 makes MYCN amplified small cell lung cancer more sensitive to ABT-263. We also demonstrated that the synergistic inhibition of JQ1/ABT-263 was mediated by the up-regulation of Bim protein through siRNA knockdown of Bim. In MYCN amplified small cell lung cancer, JQ1/ABT-263 co-treatment could significantly reduce the interaction of Bim/Bcl-2 and inhibit the interaction between Bim and Mcl-1. Importantly, JQ1/ABT-263 synergistically inhibits tumor growth in xenotransplantation models of small cell lung cancer amplified by MYCN. Our results suggest that JQ1/ABT-263 is a novel and effective targeting strategy for MYCN amplified small cell lung cancer.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
，
本文编号：2278620
[Abstract]:Small cell lung cancer is a malignant tumor with poor prognosis. Overexpression of anti-apoptotic protein Bcl-2 often occurs in small cell lung cancer, which makes it a potential therapeutic target. Previous studies have shown that ABT-263, an inhibitor of Bcl-2, has limited inhibitory effects on small cell lung cancer. In this study, we found for the first time that co-inhibition of N-Myc and Bcl-2 had strong synergistic antitumor effects in MYCN amplified small cell lung cancer. We found that JQ1, a BET inhibitor, could inhibit the expression of N-Myc protein in small cell lung cancer amplified by MYCN, and the inhibitory effect of JQ1 on N-Myc induced the expression of Bim protein in MYCN amplified small cell lung cancer. In addition, the up-regulation of Bim induced by JQ1 makes MYCN amplified small cell lung cancer more sensitive to ABT-263. We also demonstrated that the synergistic inhibition of JQ1/ABT-263 was mediated by the up-regulation of Bim protein through siRNA knockdown of Bim. In MYCN amplified small cell lung cancer, JQ1/ABT-263 co-treatment could significantly reduce the interaction of Bim/Bcl-2 and inhibit the interaction between Bim and Mcl-1. Importantly, JQ1/ABT-263 synergistically inhibits tumor growth in xenotransplantation models of small cell lung cancer amplified by MYCN. Our results suggest that JQ1/ABT-263 is a novel and effective targeting strategy for MYCN amplified small cell lung cancer.
【学位授予单位】：中国科学技术大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2
，
本文编号：2278620
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