Introduction of hypoxia-targeting p53 fusion protein for the selective therapy of non-small cell lung cancer
Introduction of hypoxia-targeting p53 fusion protein for the selective therapy of non-small cell lung cancer
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DOI：
10.4161/cbt.11.1.13960
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Wang, Yuxia
中科院分区：
文献类型：
--
作者：
Zhao, Yu;Wu, Shaoping;Wang, Yuxia
非小细胞肺癌（Non-small cell lung cancer，NSCLC）约占肺癌的85%，是世界范围内恶性肿瘤死亡的主要原因。TP 53功能障碍和缺氧是包括NSCLC在内的多种实体瘤的典型生物学特征。为开发一种高效、低毒的靶向治疗生物制剂，将HIV-1的氧依赖性降解结构域（oxygendependentdegradation domain，ODD）的最小基序与达特的基本结构域偶联，构建了一种p53融合蛋白TAT-ODD-p53，并将其移植到非小细胞肺癌（NSCLC）细胞系H1299中。结果表明，p53融合蛋白可通过p53依赖性途径，包括上调p21表达和激活caspase-3前体，诱导H1299细胞周期阻滞和/或凋亡，抑制H1299细胞生长，尤其是在体外缺氧条件下。体内实验结果表明，该蛋白能选择性地聚集在实体瘤组织的低氧区，通过与体外相似的机制抑制肿瘤生长。未见明显副作用。因此，该重组p53蛋白有可能成为NSCLC靶向治疗的良好候选物。
Non-small cell lung cancer (NSCLC), which accounts for similar to 85% of lung cancer, is the major cause of malignancy mortality around the world. TP53 dysfunction and hypoxia are the typical biological features of the diverse solid tumors, including NSCLC. To develop an effective and low cytotoxic biological agent for targeted therapy, a p53 fusion protein, which was conjugated with the minimum motif of oxygen-dependent degradation domain (ODD) and the basic domain of TAT of HIV-1 named as TAT-ODD-p53, was evaluated for the treatment of NSCLC established by grafting H1299 cell line in which TP53 is homozygously deleted. We provide the evidence that this p53 fusion protein could significantly induce the cell cycle arrest and/or apoptosis to inhibit H1299 cells' growth via p53-dependent pathways, including upregulation of p21 expression and activation of pro-caspase-3, especially under hypoxia in vitro. The results in vivo indicated that this protein could selectively accumulate in the low oxygen tension areas of solid tumor tissues, inhibiting tumor growth via a similar mechanism to that in vitro. No obvious side effects were observed. Therefore, this recombinant p53 protein is likely to become a good candidate for targeted therapy of NSCLC.