Apoptosis induced by an antagonist peptide against HPV16 E7 in vitro and in vivo via restoration of p53 |
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Authors: | Caiping Guo Kewei Liu Yi Zheng Haibo Luo Hongbo Chen Laiqiang Huang |
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Institution: | (1) School of Life Sciences, Tsinghua University, Beijing, 100084, China;(2) The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotech & BioMedicine and Division of Life Sciences, Graduate School at Shenzhen, Tsinghua University, The University Town, Shenzhen, Guangdong, 518055, China; |
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Abstract: | Human papilloma virus type 16 (HPV16) E7 is a viral oncoprotein that is believed to play a major role in cervical neoplasia.
A novel antagonist peptide against HPV16 E7 was previously selected by phage display screening and the selected peptide was
found to have anti-tumor efficacy against HPV16-positive cervical carcinoma through induction of cell cycle arrest. In the
current study, to further elucidate the mechanisms of the antagonist peptide, the effects of the peptide on apoptosis are
investigated by RT-PCR, Western blotting, MTT assay, TUNEL staining, Annexin V apoptosis assay, flow cytometry, and animal
experiments. The antagonist peptide showed obvious anti-tumor efficacy through apoptosis induction, both in HPV16-positive
cervical cancer cell lines and tumor xenografts. Our results also revealed that the peptide induced accumulation of cellular
p53 and p21, and led to HPV16 E7 protein degradation. In the case of mRNA levels, it resulted in unaltered p53 and HPV16 E7
expression, but increased expression of p21. In contrast, the induction of apoptosis and p53 reactivation effects by the selected
peptide were abolished after E7 knocked down with siRNA. These results demonstrate that the selected peptide can induce E7
degradation and lead to marked apoptosis in HPV16-related cancer cells by activating cellular p53 and its target genes, such
as p21. Furthermore, the evident therapeutic efficacy obtained from the subcutaneous tumor model experiments in nude mice
suggests a therapeutic potential for HPV16-related cancers of the selected peptide. Therefore, this specific peptide may be
used to create specific biotherapies for the treatment of HPV 16-positive cervical cancers. |
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