Document Detail

P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells.
MedLine Citation:
PMID:  20971978     Owner:  NLM     Status:  MEDLINE    
Hepatocellular carcinoma (HCC) is one of the most malignant tumours with high rate of recurrence and metastasis. In HCC, deficiency of the P16/CDK4/Rb pathway is a frequent molecular event, and transferring the P16 gene into cancer cells can induce cell cycle arrest and apoptosis, suggesting that the P16 gene is a good target in cancer gene therapy. The previous study demonstrated that P16 re-expression mediated by adenovirus within cancer cells can induce cell apoptosis and exert potent antitumour efficacy in cancer xenografts in nude mice. However, the molecular mechanism of P16-induced apoptosis in cancer cells is not clear yet. In this resulting study, we found that P16 re-expression can downregulate survivin expression in HCC cells. As a member of the inhibitors of the apoptotic gene family, survivin has been reported to be overexpressed in most common human cancers and present multiple physiological and pathological functions including cell cycle control, inhibition of cell apoptosis, regulation of cell division and induction of angiogenesis, etc. Further investigation found that P16 reactivation led to a decrease of phosphorylated Akt on Thr308 and phosphorylated survivin on Thr34, then downregulated survivin expression. The P16-mediated decrease of nuclear survivin in cancer cells limited CDK4 import into nuclei, which restrained CDK4 functions of promoting cell proliferation, then exhibited the effect of cell cycle arrest and induction of detachment-induced apoptosis (anoikis). The antitumor potency of P16 by downregulating the Akt/survivin signalling was also demonstrated in HCC xenograft models in nude mice. This new insight into P16 function would help in designing better strategies for cancer gene therapy.
Huanzhang Hu; Zhigang Li; Jie Chen; Duanming Wang; Juming Ma; Weiguo Wang; Jiang Li; Hongping Wu; Linfang Li; Mengchao Wu; Qijun Qian; Jingbo Chen; Changqing Su
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-22
Journal Detail:
Title:  Gut     Volume:  60     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-05     Completed Date:  2011-07-22     Revised Date:  2012-06-25    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  710-21     Citation Subset:  AIM; IM    
Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai 200438, China.
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MeSH Terms
Anoikis / genetics
Cell Cycle / genetics
Cell Nucleus / metabolism
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques / methods
Gene Therapy / methods
Genes, p16*
Inhibitor of Apoptosis Proteins / metabolism
Liver Neoplasms, Experimental / genetics*,  metabolism,  pathology,  prevention & control
Mice, Nude
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / genetics
Transcriptional Activation
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Reg. No./Substance:
0/BIRC5 protein, human; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Inhibitor of Apoptosis Proteins; EC Proteins c-akt; EC protein, human; EC Kinase 4

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