title: A p53-independent apoptotic mechanism of adenoviral mutant E1A was involved in its selective antitumor activity for human cancer.
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.
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fang
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.|Affiliated Hospital of Taishan Medical University, Taian, Shandong Province, 271000, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.|Cancer Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Liantao
authors.initials: L
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.|Cancer Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, China.
authors.forename: Junnian
authors.initials: J
authors.lastname: Zheng
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D045325:HCT116 Cells; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Rb; adenoviral E1A; cell apoptosis; hepatocellular carcinoma; p53