Inhibition of the p53-MDM2 interaction by adenovirus delivery of ribosomal protein L23 stabilizes p53 and induces cell cycle arrest and apoptosis in gastric cancer.
BACKGROUND
Inhibiting MDM2 activity in tumors that express wild-type (wt) p53 but have high levels of MDM2 protein has been considered an attractive anticancer strategy for many years. Previous studies revealed that human ribosomal protein L23 (RPL23) inhibited MDM2-mediated p53 degradation and thus induced p53 levels as well as its activity, suggesting that it might be a candidate for use as a gene therapy for cancer. In the present study, we evaluated whether targeting this pathway could be of therapeutic value against human gastric carcinoma.


METHODS
Gastric cancer cell lines carrying wt or mutant p53 gene were infected with adenovirus expressing RPL23 (Ad-RPL23). Cell growth assay, flow cytometry assay and morphology were used to observe the effects of Ad-RPL23 infection on tumor cells, and further, the effect of Ad-RPL23 treatment on tumor growth in vivo was investigated.


RESULTS
In vitro, adenovirus-mediated RPL23 gene transfer stabilized wt p53 by inhibiting its degradation, and thus resulted in G(1)-S cell cycle arrest and/or apoptosis of human gastric cancer MKN45 and AGS cells carrying wt p53 gene. Adenovirus-mediated RPL23 gene transfer also inhibited the growth of MKN45 tumors in subcutaneous mouse models.


CONCLUSIONS
The data obtained in the present study suggest that, through the inhibition of the p53-MDM2 interaction, adenovirus delivery of RPL23 can inhibit the proliferation of gastric cancer cells harboring wt p53 in vitro and in vivo. Exogenous RPL23-induced wt p53 stabilization and activation may be a novel therapeutic approach for patients with gastric cancer.
Zhang
Yafei
Y
State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Shi
Yongquan
Y
Li
Xiaohua
X
Du
Wenqi
W
Luo
Guanhong
G
Gou
Yawen
Y
Wang
Xin
X
Guo
Xuegang
X
Liu
Jie
J
Ding
Jie
J
Wu
Kaichun
K
Fan
Daiming
D
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D050759:Cyclin-Dependent Kinase Inhibitor p21; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C032493:ribosomal protein L17; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2