P16 reactivation induces anoikis and exhibits antitumour potency by downregulating Akt/survivin signalling in hepatocellular carcinoma cells.
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.
Laboratory of Viral & Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai 200438, China. suchangqing@gmail.com
Huanzhang
H
Hu
Zhigang
Z
Li
Jie
J
Chen
Duanming
D
Wang
Juming
J
Ma
Weiguo
W
Wang
Jiang
J
Li
Hongping
H
Wu
Linfang
L
Li
Mengchao
M
Wu
Qijun
Q
Qian
Jingbo
J
Chen
Changqing
C
Su
D000818:Animals; D023102:Anoikis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods; D019942:Genes, p16; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000077022:Survivin; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4