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Antitumor effect of recombinant replicationdefective adenovirus Adp53AIP1 and its related mechanism
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Abstract:
Objective:To investigate the antitumor effect of exogenous p53regulated apoptosisinducing protein 1（p53AIP1）and the related mechanism, so as to assess the feasibility of using p53AIP1 in tumor gene therapy. Methods: The recombinant replicationdefective adenovirus Adp53AIP1 containing p53AIP1 gene was constructed and transfected into human hepatocellular carcinoma HepG2 cell line. The effects and the relevant mechanisms of exogenous p53AIP1 gene on cell growth were examined by MTT, Western blotting, flow cytometry, rhodamine staining and electron microscopy. Nude mice were subcutaneously inoculated with Adp53AIP1infected mouse breast cancer cell line 4T1 to observe the effect of Adp53AIP1 on tumorigenesis of tumor cells. 4T1 breast cancer xenograft models were established in mice and intratumoral injections of Adp53AIP1 were given to observe the antitumor effect of Adp53AIP1. Results: Overexpression of p53AIP1 protein was confirmed in HepG2 cells infected with Adp53AIP1. Cell growth of HepG2 cells which contain wildtype p53 gene was inhibited by over 50% after infection. Flow cytometry showed transfection with p53AIP1 gene resulted in cell cycle arrest at G2/M. Results of PARP protein examination, rhodamine staining and electron microscopic observation demonstrated that p53AIP1induced obvious apoptosis in tumor cells. Moreover, the infection with Adp53AIP1 significantly inhibited the tumorigenesis of 4T1 cells in vivo （P<0.01）and the growth of tumors in vivo after intratumorial injection（P<0.05）. Furthermore, Western blotting and RTPCR confirmed that Adp53AIP1 had no influence on p53 mRNA expression and downregulated mdm2gene and protein; it also upregulated P53 protein expression. In addition, Adp53AIP1 could regulate cell cyclerelated proteins and apoptosisrelated proteins such as P21. Conclusions: Adp53AIP1 possess obvious tumor inhibitory effect in vitro and in vivo; the mechanism is related to its regulation of P53 protein, cell cycle and apoptosisrelated proteins. p53AIP1 might have a future in tumor gene therapy.
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Supported by the Major State Basic Research Development Program of China (No. 2002CB513105)
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