A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer.
A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer.
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腺病毒突变体E1A的独立于p53的凋亡机制参与其对人类癌症的选择性抗肿瘤活性
DOI：
10.18632/oncotarget.10221
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Fang L;Cheng Q;Zhao J;Ge Y;Zhu Q;Zhao M;Zhang J;Zhang Q;Li L;Liu J;Zheng J
腺病毒E1a的保守区(CR)是破坏pRb-E2F转录因子复合体和诱导S期所必需的。我们构建了一个缺失Rb结合能力的突变腺病毒E1a(E1A30-60aa和120-127aa缺失，mE1a)，并对其体内外抗肿瘤活性进行了研究。ME1a对肿瘤细胞的抑制作用与野生型E1a相同，对正常细胞无细胞毒作用。虽然mE1a以与E1a相同的方式阻断肿瘤细胞周期，但与E1a相比，mE1a在正常细胞中对细胞周期的调节作用不同，这可能是其选择性抗肿瘤活性的原因之一。E1a和mE1a积聚了失活的p53，降低了mdm2、CDKN1a(又称p21)的表达，增加了p21‘S的核分布，并以P53不依赖的方式诱导肿瘤细胞凋亡。此外，E1a或mE1a显著抑制皮下移植肝癌模型中的肿瘤生长。特别是，mE1A治疗的荷瘤小鼠的存活率高于E1A治疗的小鼠。结果表明，突变型腺病毒E1a能显著诱导肿瘤细胞凋亡，并具有选择性抑瘤作用。腺病毒E1a突变体的发现为E1a在感染过程中的复杂活动提供了一种新的机制。
The conserved regions (CR) of adenoviral E1A had been shown to be necessary for disruption of pRb-E2F transcription factor complexes and induction of the S phase. Here we constructed a mutant adenoviral E1A with Rb-binding ability absent (E1A 30-60aa and 120-127aa deletion, mE1A) and investigated its antitumor capacities in vitro and in vivo. The mE1A suppressed the viability of tumor cells as efficiently as the wild type E1A, and there was no cytotoxic effect on normal cells. Although the mE1A arrested tumor cell cycle with the same manner as E1A, the former played a different role on cell cycle regulation compared with E1A in normal cells, which might contribute to its selective antitumor activity. E1A and mE1A had accumulated inactive p53, decreased the expression of mdm2, Cdkn1a (also named p21), increased p21's nuclear distribution and induced tumor cell apoptosis in a p53-indenpent manner. Further, E1A or mE1A significantly suppressed tumor growth in subcutaneous hepatocellular carcinoma xenograft models. Especially, tumor-bearing mice treated with mE1A had higher survival rate than those treated with E1A. Our data demonstrated that mutant adenoviral E1A significantly induced tumor cell apoptosis in a p53-indenpednt manner and had selective tumor suppressing ability. The observations of adenoviral E1A mutant had provided a novel mechanism for E1A's complex activities during infection.