Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E

Kangsheng Tu; Xin Zheng; Zhenyu Zhou; Chao Li; Jing Zhang; Jie Gao; Yingmin Yao; Qingguang Liu

doi:10.1371/journal.pone.0068574

Recombinant human adenovirus-p53 injection induced apoptosis in hepatocellular carcinoma cell lines mediated by p53-Fbxw7 pathway, which controls c-Myc and cyclin E

PLoS One. 2013 Jul 1;8(7):e68574. doi: 10.1371/journal.pone.0068574. Print 2013.

Authors

Kangsheng Tu¹, Xin Zheng, Zhenyu Zhou, Chao Li, Jing Zhang, Jie Gao, Yingmin Yao, Qingguang Liu

Affiliation

¹ Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Abstract

F-box and WD repeat domain-containing 7 (Fbxw7/hAgo/hCdc4/Fbw7) is a p53-dependent tumor suppressor and leads to ubiquitination-mediated suppression of several oncoproteins including c-Myc, cyclin E, Notch, c-Jun and others. Our previous study has indicated that low expression of Fbxw7 was negatively correlated with c-Myc, cyclin E and mutant-p53 in hepatocellular carcinoma (HCC) tissues. But the role and mechanisms of Fbxw7 in HCC are still unknown. Here, we investigated the function of Fbxw7 in HCC cell lines and the anti-tumor activity of recombinant human adenovirus-p53 injection (rAd-p53, Gendicine) administration in vitro and in vivo. Fbxw7-specific siRNA enhanced expression of c-Myc and cyclin E proteins and increased proliferation in cell culture. rAd-p53 inhibited tumor cell growth with Fbxw7 upregulation and c-Myc and cyclin E downregulation in vitro and a murine HCC model. This effect could be partially reverted using Fbxw7-specific siRNA. Here, we suggest that the activation of Fbxw7 by adenoviral delivery of p53 leads to increased proteasomal degradation of c-Myc and cyclin E enabling growth arrest and apoptosis. Addressing this pathway, we identified that rAd-p53 could be a potential therapeutic agent for HCC.

Publication types

Research Support, Non-U.S. Gov't
Retracted Publication

MeSH terms

Adenoviruses, Human / genetics*
Animals
Apoptosis
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / therapy*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cyclin E / genetics
Cyclin E / metabolism*
F-Box Proteins / genetics
F-Box Proteins / metabolism*
F-Box-WD Repeat-Containing Protein 7
Female
Gene Expression Regulation, Neoplastic
Genetic Therapy
Humans
Liver / metabolism
Liver / pathology
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / therapy*
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism*
RNA Interference
Signal Transduction
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / therapeutic use*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Cell Cycle Proteins
Cyclin E
F-Box Proteins
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
Proto-Oncogene Proteins c-myc
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases

Grants and funding

This study was supported by a grant from the National Natural Science Foundation of China (no. 81272645 and no. 81071897) and the Scholarship Award for Excellent Doctoral Student granted by Ministry of Education. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.