A single recombinant adenovirus expressing p53 and p21-targeting artificial microRNAs efficiently induces apoptosis in human cancer cells
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Published on: January 4, 2012
Masashi Idogawa1, Yasushi Sasaki, Hiromu Suzuki
1Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo, Japan.
Purpose:
Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. The activation of p53 induces either cell cycle arrest or apoptosis. Cell cycle arrest in response to p53 activation is mediated primarily through the induction of the cyclin-dependent kinase inhibitor p21. Because p21 also has an inhibitory effect on p53-mediated apoptosis, the suppression of p53-induced p21 expression would be expected to result in the preferential induction of apoptosis. However, p21 also has tumor-suppressive properties. In this study, we developed an adenovirus vector that expresses p53 and suppresses p21 simultaneously to enhance p53-mediated apoptosis.
Experimental Design:
We constructed a replication-deficient recombinant adenovirus (Ad-p53/miR-p21) that enabled cocistronic expression of the p53 protein and artificial microRNAs that targeted p21, and examined the therapeutic effectiveness of this vector in vitro and in vivo.
Results:
The levels of p21 were significantly attenuated following infection with Ad-p53/miR-p21. In colorectal and hepatocellular carcinoma cells, infection with Ad-p53/miR-p21 augmented apoptosis as compared with an adenovirus that expressed p53 alone (Ad-p53/miR-control). Ad-p53/miR-p21 also significantly increased the chemosensitivity of cancer cells to adriamycin (doxorubicin). In a xenograft tumor model in nude mice, tumor volume was significantly decreased following the direct injection of Ad-p53/miR-p21 into the tumor, as compared with the injection of Ad-p53/miR-control.
Conclusion:
These results suggest that adenovirus-mediated transduction of p53 and p21-specific microRNAs may be useful for gene therapy of human cancers.
Insights
This study developed a novel gene therapy vector to enhance cancer apoptosis. The adenovirus vector simultaneously delivers p53 and suppresses p21, improving therapeutic outcomes in preclinical cancer models.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Gene Therapy
Background:
- Gene transfer involving p53 shows promise for cancer therapy but has variable responses.
- p53 activation induces cell cycle arrest (via p21) or apoptosis.
- p21 inhibits p53-mediated apoptosis, suggesting its suppression could enhance cell death.
Purpose of the Study:
- To develop an adenovirus vector for simultaneous p53 expression and p21 suppression.
- To enhance p53-mediated apoptosis in cancer cells using this novel vector.
Main Methods:
- Constructed a replication-deficient adenovirus (Ad-p53/miR-p21) for co-expression of p53 and p21-targeting microRNAs.
- Evaluated the therapeutic efficacy of Ad-p53/miR-p21 in vitro (cancer cell lines) and in vivo (xenograft models).
Main Results:
- Ad-p53/miR-p21 significantly reduced p21 levels.
- Enhanced apoptosis in colorectal and hepatocellular carcinoma cells compared to Ad-p53 alone.
- Increased cancer cell chemosensitivity to doxorubicin and reduced tumor volume in vivo.
Conclusions:
- Adenovirus-mediated delivery of p53 and p21-specific microRNAs shows potential for cancer gene therapy.
- This approach may overcome limitations of p53-based therapies by promoting apoptosis.
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