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Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and
M Bouvet1, L M Ellis, M Nishizaki
1Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
Recent studies have indicated that angiogenesis may be regulated, in part, by p53 tumor suppressor gene function. We hypothesized that wild-type p53 replacement would down-regulate vascular endothelial growth factor (VEGF) expression and inhibit angiogenesis. KM12L4 and SW620, human colon cancer cell lines with p53 mutations, were transduced with a replication-defective adenoviral vector containing the wild-type p53 gene (Ad5/CMV/p53). Reverse transcription-PCR confirmed the presence of p53 in Ad5/CMV/p53-transduced cells. Transduction of colon cancer cells with wild-type p53 decreased VEGF RNA expression compared with that of controls. The decrease in VEGF expression in SW620 cells was dose dependent, with a 49% decrease observed at a multiplicity of infection of 50, and a 71% decrease observed at a multiplicity of infection of 100. Similar effects were seen in KM12L4 cells. VEGF supernatant protein levels were significantly reduced compared with those in nontransduced controls 48 h after the introduction of wild-type p53. Ad5/CMV/p53 inhibited tumor cell-induced angiogenesis in vivo. Restoration of wild-type p53 expression may decrease tumor growth by inhibiting the angiogenic response. These findings may explain, in part, the bystander effect seen with p53 tumor suppressor gene therapy.
Insights
Restoring wild-type p53 gene function in colon cancer cells significantly reduced vascular endothelial growth factor (VEGF) expression and inhibited angiogenesis. This suggests a new therapeutic strategy targeting tumor growth by controlling blood vessel formation.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
- The p53 tumor suppressor gene plays a critical role in cellular processes, and its dysfunction is common in various cancers.
- Emerging evidence suggests a link between p53 activity and the regulation of angiogenesis, particularly through vascular endothelial growth factor (VEGF).
Purpose of the Study:
- To investigate the effect of wild-type p53 gene replacement on vascular endothelial growth factor (VEGF) expression in human colon cancer cell lines.
- To determine if restoring p53 function can inhibit angiogenesis mediated by tumor cells.
- To explore the potential therapeutic implications of p53-mediated regulation of VEGF in cancer treatment.
Main Methods:
- Human colon cancer cell lines (KM12L4 and SW620) with p53 mutations were transduced with a replication-defective adenoviral vector carrying the wild-type p53 gene (Ad5/CMV/p53).
- Reverse transcription-polymerase chain reaction (RT-PCR) was used to confirm p53 expression in transduced cells.
- VEGF RNA and protein levels were quantified, and in vivo angiogenesis assays were performed to assess the impact of p53 restoration.
Main Results:
- Successful transduction of colon cancer cells with Ad5/CMV/p53 led to the expression of wild-type p53.
- Transduction with wild-type p53 significantly decreased VEGF RNA expression in a dose-dependent manner in both cell lines.
- VEGF protein levels in the supernatant were substantially reduced post-transduction, and tumor cell-induced angiogenesis in vivo was inhibited.
Conclusions:
- Restoration of wild-type p53 expression effectively down-regulates VEGF expression and inhibits angiogenesis in colon cancer cells.
- This suggests that targeting the p53 pathway could be a viable strategy to control tumor growth by suppressing the angiogenic response.
- The findings provide a molecular basis for understanding the bystander effect observed in p53 tumor suppressor gene therapy and highlight its potential in cancer treatment.
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