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Adenovirus Ad-p53AIP1-mediated gene therapy and its regulation of p53-MDM2 interactions
Yunbo Jiang1, Huihua Chen, Haiquan Jia
1Department of Pathobiology, Institute of Basic Medical Sciences, Beijing 100850, P.R. China ;
Abstract:
We generated replication-defective adenovirus Ad-p53AIP1 and studied its anti-tumor efficacy both in vitro and in vivo. We demonstrated that Ad-p53AIP1 infection elicited high levels of p53AIP1 expression in cancer cells. We also found that Ad-p53AIP1 expression induced marked apoptosis and cell cycle arrest in HepG2 cells. Moreover, Ad-p53AIP1 infection significantly inhibited the tumorigenesis of 4T1 mouse mammary cancer cells in vivo. In particular, we discovered that p53AIP1 overexpression up-regulated the protein levels of p53 in HepG2 cells, which was accompanied by down-regulation of MDM2 mRNA and protein, suggesting an interaction between MDM2 and p53 in p53AIP1-induced apoptosis and cell cycle arrest. Our data demonstrated the feasibility of Ad-p53AIP1-mediated cancer gene therapy. p53AIP1-induced up-regulation of p53 protein through MDM2 suggests that p53AIP1 gene therapy may be more advantageous in tumors expressing high levels of oncoprotein MDM2 or having a mutation in MDM2 inhibitor p16INK4.
Insights
Replication-defective adenovirus Ad-p53AIP1 effectively targets cancer cells, inducing apoptosis and inhibiting tumor growth. This gene therapy approach shows promise, particularly for tumors with high MDM2 levels.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- The tumor suppressor protein p53 plays a critical role in cell cycle regulation and apoptosis.
- MDM2 is an oncoprotein that inhibits p53 activity, and its dysregulation is common in cancer.
- p53AIP1 is a p53-inducible gene involved in apoptosis.
Purpose of the Study:
- To evaluate the anti-tumor efficacy of a replication-defective adenovirus carrying the p53AIP1 gene (Ad-p53AIP1).
- To investigate the molecular mechanisms underlying Ad-p53AIP1-mediated anti-cancer effects.
- To assess the potential of Ad-p53AIP1 as a cancer gene therapy strategy.
Main Methods:
- Generation of replication-defective adenovirus Ad-p53AIP1.
- In vitro studies using HepG2 cells to assess p53AIP1 expression, apoptosis, and cell cycle arrest.
- In vivo studies using 4T1 mouse mammary cancer cells to evaluate tumor inhibition.
- Analysis of p53 and MDM2 protein and mRNA levels.
Main Results:
- Ad-p53AIP1 infection led to high p53AIP1 expression in cancer cells.
- Ad-p53AIP1 induced significant apoptosis and cell cycle arrest in HepG2 cells.
- Ad-p53AIP1 significantly inhibited tumor growth of 4T1 cells in vivo.
- p53AIP1 overexpression upregulated p53 protein and downregulated MDM2 in HepG2 cells, suggesting a role for MDM2 in the observed effects.
Conclusions:
- Ad-p53AIP1 demonstrates significant anti-tumor efficacy both in vitro and in vivo.
- The mechanism involves p53AIP1-mediated upregulation of p53, potentially through interaction with MDM2.
- Ad-p53AIP1-mediated gene therapy is feasible and may be particularly effective in tumors with high MDM2 expression or p16INK4 mutations.
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