Oncotarget

Research Papers:

A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer

Lin Fang, Qian Cheng, Jingjing Zhao, Yan Ge, Qi Zhu, Min Zhao, Jie Zhang, Qi Zhang, Liantao Li, Junjie Liu _ and Junnian Zheng

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Oncotarget. 2016; 7:48309-48320. https://doi.org/10.18632/oncotarget.10221

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Abstract

Lin Fang1, Qian Cheng1, Jingjing Zhao1, Yan Ge1, Qi Zhu1, Min Zhao1,2, Jie Zhang1, Qi Zhang1, Liantao Li1,3, Junjie Liu1, Junnian Zheng1,3,4

1Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China

2Affiliated Hospital of Taishan Medical University, Taian, Shandong Province, 271000, China

3Cancer Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China

4Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China

Correspondence to:

Junnian Zheng, email: [email protected]

Keywords: adenoviral E1A, Rb, p53, cell apoptosis, hepatocellular carcinoma

Received: December 03, 2015     Accepted: June 06, 2016     Published: June 22, 2016

ABSTRACT

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.


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