title: Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest.
abstract: Human papilloma virus (HPV) infection represents an emerging risk factor in head and neck squamous cell carcinoma (HNSCC). In contrast to HPV-negative HNSCC, most cases of HPV-positive HNSCC encode wild-type p53, although the p53 protein in these cells is rapidly degraded via HPV E6-mediated ubiquitination and subsequent proteasomal degradation. This unique feature of HPV-positive HNSCC has raised hope that liberation of wild-type p53 from the E6 protein may have therapeutic benefit in this disease. Indeed, suppression of E6 expression promotes apoptosis in HPV-positive HNSCC cell lines. However, the role of p53 in mediating this cell death has not been determined. Here, we demonstrate that siRNAs targeting the E6/E7 RNA, or treatment with the proteasome inhibitor bortezomib, resulted in upregulation of functional p53 and p53 gene targets in three HPV-positive HNSCC cell lines, but not in HPV-negative HNSCC cells. Apoptosis induced by E6/E7 siRNA in HPV-positive cells was found to be dependent on p53, while bortezomib-induced cell death was modestly p53-dependent. Treatment with subtoxic doses of bortezomib led to cell cycle arrest in HPV-positive, but not HPV-negative HNSCC cells. Moreover, this cell cycle arrest was mediated by p53 and the cell cycle inhibitor p21, the product of a p53 target gene. Collectively, these findings establish that wild-type p53 encoded by HPV-positive HNSCC cells, once liberated from HPV E6, can play important roles in promoting apoptosis and cell cycle arrest.
authors: Department of Medicine, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors: Changyou
authors: C
authors: Li
authors: Daniel E
authors: DE
authors: Johnson
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000821:virology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000821:virology; D052162:Human papillomavirus 16; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D050725:Papillomavirus E7 Proteins / Q000235:genetics*; D030361:Papillomavirus Infections; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D001897:Boronic Acids; D050759:Cyclin-Dependent Kinase Inhibitor p21; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
keywords: E6; E7; HPV16; apoptosis; bortezomib; cell cycle arrest; head and neck squamous cell carcinoma; p21; p53