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

Fang,Henghu; Kang,Jingbo; Du,Rui; Zhao,Xiangfei; Zhang,Xinhong; Ren,Dongqing; Zhang,Yafei; Lu,Zejun; Wu,Shanshan; Zheng,Wei; Wen,Juyi

doi:10.3892/or.2015.4026

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

Authors:
- Henghu Fang
- Jingbo Kang
- Rui Du
- Xiangfei Zhao
- Xinhong Zhang
- Dongqing Ren
- Yafei Zhang
- Zejun Lu
- Shanshan Wu
- Wei Zheng
- Juyi Wen
View Affiliations

Affiliations: Department of Radiation Oncology, Navy General Hospital, Beijing, P.R. China, Department of Radiation Medicine and The Ministry of Education, Key Laboratory of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, P.R. China, Department of Gastroenterology, General Hospital of the Air Force, PLA, Beijing, P.R. China
Published online on: June 4, 2015 https://doi.org/10.3892/or.2015.4026
Pages: 763-770

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Selivanova G: Wild type p53 reactivation: from lab bench to clinic. FEBS Lett. 588:2628–2638. 2014. View Article : Google Scholar : PubMed/NCBI
2	Khoo KH, Verma CS and Lane DP: Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 13:217–236. 2014. View Article : Google Scholar : PubMed/NCBI
3	Kruse JP and Gu W: Modes of p53 regulation. Cell. 137:609–622. 2009. View Article : Google Scholar : PubMed/NCBI
4	Freedman DA, Wu L and Levine AJ: Functions of the MDM2 oncoprotein. Cell Mol Life Sci. 55:96–107. 1999. View Article : Google Scholar : PubMed/NCBI
5	Wang W and El-Deiry WS: Restoration of p53 to limit tumor growth. Curr Opin Oncol. 20:90–96. 2008. View Article : Google Scholar
6	Momand J, Jung D, Wilczynski S and Niland J: The MDM2 gene amplification database. Nucleic Acids Res. 26:3453–3459. 1998. View Article : Google Scholar : PubMed/NCBI
7	Zhao Y, Aguilar A, Bernard D and Wang S: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 inhibitors) in clinical trials for cancer treatment. J Med Chem. 58:1038–1052. 2015. View Article : Google Scholar
8	Lu C and El-Deiry WS: Targeting p53 for enhanced radio- and chemo-sensitivity. Apoptosis. 14:597–606. 2009. View Article : Google Scholar : PubMed/NCBI
9	Dai MS, Zeng SX, Jin Y, Sun XX, David L and Lu H: Ribosomal protein L23 activates p53 by inhibiting MDM2 function in response to ribosomal perturbation but not to translation inhibition. Mol Cell Biol. 24:7654–7668. 2004. View Article : Google Scholar : PubMed/NCBI
10	Jin A, Itahana K, O’Keefe K and Zhang Y: Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 24:7669–7680. 2004. View Article : Google Scholar : PubMed/NCBI
11	Pocard M, Chevillard S, Villaudy J, Poupon MF, Dutrillaux B and Remvikos Y: Different p53 mutations produce distinct effects on the ability of colon carcinoma cells to become blocked at the G1/S boundary after irradiation. Oncogene. 12:875–882. 1996.PubMed/NCBI
12	Shi MD, Lin HH, Lee YC, Chao JK, Lin RA and Chen JH: Inhibition of cell-cycle progression in human colorectal carcinoma Lovo cells by andrographolide. Chem Biol Interact. 174:201–210. 2008. View Article : Google Scholar : PubMed/NCBI
13	Zhang NH, Song LB, Wu XJ, Li RP, Zeng MS, Zhu XF, Wan DS, Liu Q, Zeng YX and Zhang XS: Proteasome inhibitor MG-132 modifies coxsackie and adenovirus receptor expression in colon cancer cell line Lovo. Cell Cycle. 7:925–933. 2008. View Article : Google Scholar : PubMed/NCBI
14	Kim HJ, Cho HI, Han YH, Park SY, Kim DW, Lee DG, Kim JH, Shin WS, Paik SY, Kim CC, et al: Efficient transduction with recombinant adenovirus in EBV-transformed B lymphoblastoid cell lines. J Biochem Mol Biol. 37:376–382. 2004. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Shi Y, Li X, Du R, Luo G, Xia L, Du W, Chen B, Zhai H, Wu K, et al: Proteasome inhibitor MG132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp. Cancer Biol Ther. 7:540–546. 2008. View Article : Google Scholar : PubMed/NCBI
16	Li X, Zhang Y, Xiong C, Jin H, Jing B, Zhang Y and Fan D: Overexpression of a new gene P28GANK confers multidrug resistance of gastric cancer cells. Cancer Invest. 27:129–139. 2009. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Chen Y, Dilley J, Arroyo T, Ko D, Working P and Yu DC: Carcinoembryonic antigen-producing cell-specific oncolytic adenovirus, OV798, for colorectal cancer therapy. Mol Cancer Ther. 2:1003–1009. 2003.PubMed/NCBI
18	Cao G, Kuriyama S, Gao J, Kikukawa M, Cui L, Nakatani T, Zhang X, Tsujinoue H, Pan X, Fukui H, et al: Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene directed by the carcinoembryonic antigen promoter. Gene Ther. 6:83–90. 1999. View Article : Google Scholar : PubMed/NCBI
19	Schrewe H, Thompson J, Bona M, Hefta LJ, Maruya A, Hassauer M, Shively JE, von Kleist S and Zimmermann W: Cloning of the complete gene for carcinoembryonic antigen: analysis of its promoter indicates a region conveying cell type-specific expression. Mol Cell Biol. 10:2738–2748. 1990.PubMed/NCBI
20	Qiao J, Doubrovin M, Sauter BV, Huang Y, Guo ZS, Balatoni J, Akhurst T, Blasberg RG, Tjuvajev JG, Chen SH, et al: Tumor-specific transcriptional targeting of suicide gene therapy. Gene Ther. 9:168–175. 2002. View Article : Google Scholar : PubMed/NCBI
21	Ueda K, Iwahashi M, Nakamori M, Nakamura M, Matsuura I, Ojima T and Yamaue H: Improvement of carcinoembryonic antigen-specific prodrug gene therapy for experimental colon cancer. Surgery. 133:309–317. 2003. View Article : Google Scholar : PubMed/NCBI
22	Dabrowska A, Szary J, Kowalczuk M, Szala S and Ugorski M: CEA-negative glioblastoma and melanoma cells are sensitive to cytosine deaminase/5-fluorocytosine therapy directed by the carcinoembryonic antigen promoter. Acta Biochim Pol. 51:723–732. 2004.PubMed/NCBI
23	Chen X, Bargonetti J and Prives C: p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. Cancer Res. 55:4257–4263. 1995.PubMed/NCBI
24	Yu J and Zhang L: No PUMA, no death: implications for p53-dependent apoptosis. Cancer Cell. 4:248–249. 2003. View Article : Google Scholar : PubMed/NCBI
25	Sobrero A, Kerr D, Glimelius B, Van Cutsem E, Milano G, Pritchard DM, Rougier P and Aapro M: New directions in the treatment of colorectal cancer: a look to the future. Eur J Cancer. 36:559–566. 2000. View Article : Google Scholar : PubMed/NCBI
26	Kuribayashi K, Mayes PA and El-Deiry WS: What are caspases 3 and 7 doing upstream of the mitochondria? Cancer Biol Ther. 5:763–765. 2006. View Article : Google Scholar : PubMed/NCBI
27	Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI
28	Rayburn E, Zhang R, He J and Wang H: MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets. 5:27–41. 2005. View Article : Google Scholar : PubMed/NCBI
29	Shangary S and Wang S: Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol. 49:223–241. 2009. View Article : Google Scholar :
30	Wang W, Rastinejad F and El-Deiry WS: Restoring p53-dependent tumor suppression. Cancer Biol Ther. 2(Suppl 1): S55–S63. 2003. View Article : Google Scholar : PubMed/NCBI
31	Deng X, Kim M, Vandier D, Jung YJ, Rikiyama T, Sgagias MK, Goldsmith M and Cowan KH: Recombinant adenovirus-mediated p14(ARF) overexpression sensitizes human breast cancer cells to cisplatin. Biochem Biophys Res Commun. 296:792–798. 2002. View Article : Google Scholar : PubMed/NCBI
32	Hemmati PG, Gillissen B, von Haefen C, Wendt J, Stärck L, Güner D, Dörken B and Daniel PT: Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis. Oncogene. 21:3149–3161. 2002. View Article : Google Scholar : PubMed/NCBI
33	Kaeser MD, Pebernard S and Iggo RD: Regulation of p53 stability and function in HCT116 colon cancer cells. J Biol Chem. 279:7598–7605. 2004. View Article : Google Scholar
34	Sun XX, Dai MS and Lu H: 5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. J Biol Chem. 282:8052–8059. 2007. View Article : Google Scholar : PubMed/NCBI
35	Wang H, Oliver P, Zhang Z, Agrawal S and Zhang R: Chemo-sensitization and radiosensitization of human cancer by antisense anti-MDM2 oligonucleotides: in vitro and in vivo activities and mechanisms. Ann NY Acad Sci. 1002:217–235. 2003. View Article : Google Scholar
36	Gu L, Findley HW and Zhou M: MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia. Blood. 99:3367–3375. 2002. View Article : Google Scholar : PubMed/NCBI
37	Cheney MD, McKenzie PP, Volk EL, Fan L and Harris LC: MDM2 displays differential activities dependent upon the activation status of NFkappaB. Cancer Biol Ther. 7:38–44. 2008. View Article : Google Scholar
38	Shen HM and Tergaonkar V: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis. 14:348–363. 2009. View Article : Google Scholar : PubMed/NCBI