Growth inhibitory effect of adenovirus-mediated tissue-targeted expression of ribosomal protein L23 on human colorectal carcinoma cells.

Abstract

A large body of evidence has established murine double minute 2 (MDM2) as a crucial negative regulator of p53 and the major suppressor of p53 function in tumors with wild-type (wt)-p53. Therefore, by inhibiting MDM2 one may reactivate p53 in tumor cells, leading to their demise. Previous studies revealed that ribosomal protein L23 (RPL23) inhibited MDM2-mediated p53 ubiquitination through direct binding to MDM2, and subsequently induced the p53 level as well as its activity, suggesting that it may be a candidate for use in tumor gene therapy. In the present study, we developed a recombinant adenoviral vector expressing the RPL23 gene under control of the carcinoembryonic antigen (CEA) promoter (rAd/CEA-RPL23), and using an in vitro system with cultured human colorectal carcinoma LoVo cells harboring the wt-p53 gene, we proved that rAd/CEA-RPL23 infection could induce the accumulation of endogenous wt-p53 protein and thus lead to the inhibition of tumor cell growth via inducing cell cycle arrest and apoptosis. In vivo treatment of rAd/CEA-RPL23 also exhibited a significant inhibitory effect on tumor growth in nude mice bearing LoVo xenografts. Furthermore, we showed that rAd/CEA-RPL23 synergized with classic chemotherapeutic agent 5-fluorouracil (5-FU) and enhanced its activity against LoVo cells in vivo and in vitro. Taken together, the data presented here suggest that CEA promoter-targeted exogenous RPL23 expression could be of therapeutic value against human colorectal carcinoma that retains wt-p53.

• Authors: Henghu Fang, Jingbo Kang, Rui Du, Xiangfei Zhao, Xinhong Zhang, Dongqing Ren, Yafei Zhang, Zejun Lu, Shanshan Wu, Wei Zheng, Juyi Wen
• Journal: Oncology reports (Oncol Rep) Vol. 34 Issue 2 Pg. 763-70 (Aug 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 26044651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinoembryonic Antigen
• Ribosomal Proteins
• Tumor Suppressor Protein p53
• ribosomal protein L17
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Apoptosis (genetics)
• Carcinoembryonic Antigen (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Colorectal Neoplasms (genetics, pathology, therapy)
• Gene Expression Regulation, Neoplastic
• Genetic Therapy
• Genetic Vectors
• Humans
• Mice
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• Ribosomal Proteins (biosynthesis, genetics)
• Tumor Suppressor Protein p53 (biosynthesis, genetics)
• Ubiquitination (genetics)