title: Induction of dormancy in hypoxic human papillomavirus-positive cancer cells.
abstract: Oncogenic human papillomaviruses (HPVs) are closely linked to major human malignancies, including cervical and head and neck cancers. It is widely assumed that HPV-positive cancer cells are under selection pressure to continuously express the viral E6/E7 oncogenes, that their intracellular p53 levels are reconstituted on E6/E7 repression, and that E6/E7 inhibition phenotypically results in cellular senescence. Here we show that hypoxic conditions, as are often found in subregions of cervical and head and neck cancers, enable HPV-positive cancer cells to escape from these regulatory principles: E6/E7 is efficiently repressed, yet, p53 levels do not increase. Moreover, E6/E7 repression under hypoxia does not result in cellular senescence, owing to hypoxia-associated impaired mechanistic target of rapamycin (mTOR) signaling via the inhibitory REDD1/TSC2 axis. Instead, a reversible growth arrest is induced that can be overcome by reoxygenation. Impairment of mTOR signaling also interfered with the senescence response of hypoxic HPV-positive cancer cells toward prosenescent chemotherapy in vitro. Collectively, these findings indicate that hypoxic HPV-positive cancer cells can induce a reversible state of dormancy, with decreased viral antigen synthesis and increased therapeutic resistance, and may serve as reservoirs for tumor recurrence on reoxygenation.
authors.affiliation: Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Hoppe-Seyler
authors.affiliation: Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Bossler
authors.affiliation: Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lohrey
authors.affiliation: Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bulkescher
authors.affiliation: Viral Transformation Mechanisms (F030), German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rösl
authors.affiliation: Department of Gynecology, Jena University Hospital, D-07743 Jena, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Jansen
authors.affiliation: Department of Radiooncology and Radiotherapy, Mainz University Medical Center, D-55131 Mainz, Germany.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Mayer
authors.affiliation: Department of Radiooncology and Radiotherapy, Mainz University Medical Center, D-55131 Mainz, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
authors.affiliation: Department of Gynecology, Jena University Hospital, D-07743 Jena, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.affiliation: Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, D-69120 Heidelberg, Germany; hoppe-seyler@dkfz.de.
authors.forename: Felix
authors.initials: F
authors.lastname: Hoppe-Seyler
mesh_terms: D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D000860:Hypoxia; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16
keywords: cervical cancer; human papillomavirus; hypoxia; mTOR; tumor virus