Co-transduction of ribosomal protein L23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in human gastric cancer.

Abstract

Induction of murine double minute 2 (MDM2) expression is thought to be a determinant of resistance to p53 gene therapy for cancer. Previous studies have revealed that ribosomal protein L23 (RPL23) inhibits MDM2-mediated p53 degradation through direct binding to MDM2. In addition, ectopically expressed RPL23 was reported to interact with MDM2 in both the nucleus and cytoplasm, by which RPL23 indirectly inhibited MDM2-p53 binding. Based on the known molecular properties of the RPL23 protein, it was speculated that co-transduction of RPL23 may protect wild‑type p53 protein from MDM2-mediated inactivation and, thus, improve the effect of delivering therapeutic exogenous p53. To test this hypothesis, we constructed a bicistronic adenoviral vector expressing both the RPL23 and p53 genes (Ad-RPL23/p53) and compared its tumor-suppressor activity in human gastric cancer with that of a single gene vector for p53 (Ad-p53). In the in vivo and in vitro experiments, we observed that treatment with Ad-RPL23/p53 resulted in a stronger antitumor response compared to that obtained using Ad-p53. Moreover, the antitumor response of the bicistronic adenovirus was obtained not only in MGC803 cells (endogenous mutant p53) but also in MKN45 cells (endogenous wild‑type p53) which were initially resistant to p53 gene transfer, indicating that co-transduction of RPL23 also expanded the utility of p53 gene therapy. Furthermore, in an orthotopic nude mouse model of human gastric cancer, we found that the survival benefit was greater after Ad-RPL23/p53 treatment than after Ad-p53. Taken together, the data presented here demonstrate that co-transduction of RPL23 enhances the therapeutic efficacy of adenoviral-mediated p53 gene transfer in models of human gastric cancer and support the use of this strategy for cancer treatment.

• Authors: Ya-Fei Zhang, Bi-Cheng Zhang, An-Ran Zhang, Ting-Ting Wu, Jian Liu, Li-Fang Yu, Wei-Xing Wang, Jian-Fei Gao, Dian-Chun Fang, Zhi-Guo Rao
• Journal: Oncology reports (Oncol Rep) Vol. 30 Issue 4 Pg. 1989-95 (Oct 2013) ISSN: 1791-2431 [Electronic] Greece
• PMID: 23933826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BBC3 protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• MRPL23 protein, human
• Mitochondrial Proteins
• Proto-Oncogene Proteins
• RNA-Binding Proteins
• Ribosomal Proteins
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Adenoviridae (genetics)
• Animals
• Apoptosis (genetics)
• Apoptosis Regulatory Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (genetics)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Genetic Therapy (methods)
• Genetic Vectors
• Heterografts
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondrial Proteins (genetics)
• Neoplasm Transplantation
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• RNA-Binding Proteins
• Ribosomal Proteins (genetics)
• Stomach Neoplasms (genetics, therapy)
• Transduction, Genetic
• Tumor Suppressor Protein p53 (genetics)