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Induction of dormancy in hypoxic human papillomavirus-positive cancer cells

K. Hoppe‐Seyler,Felicitas Bossler,Claudia Lohrey,Julia Bulkescher,F. Rösl,L. Jansen,A. Mayer,P. Vaupel,M. Dürst,F. Hoppe-Seyler

Published 2017 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Human papillomaviruses (HPVs) are major human carcinogens. It is widely assumed that HPV-positive tumor cells must sustain viral E6/E7 oncogene expression to continuously block the tumor-suppressive senescence response of the host cell. Consequently, E6/E7 are considered attractive therapeutic targets for immunotherapy or for functional inhibition. Here we show that hypoxic conditions, as often found in HPV-positive cancers, allow the cells to induce a dormant state in which E6/E7 is down-regulated but induction of senescence is avoided. Instead, a reversible growth arrest is induced that can be overcome by reoxygenation. As a consequence, hypoxic HPV-positive cancer cells are protected against chemotherapy as well as against virus-specific therapeutic approaches, and may serve as reservoirs for cancer recurrence on reoxygenation. 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.

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