Repression of Human Papillomavirus Oncogene Expression under Hypoxia Is Mediated by PI3K/mTORC2/AKT Signaling.
Cell Line, Tumor
Down-Regulation
Host-Pathogen Interactions
Humans
Hypoxia
Mechanistic Target of Rapamycin Complex 2
/ metabolism
Oncogene Proteins, Viral
/ biosynthesis
Papillomaviridae
/ physiology
Phosphatidylinositol 3-Kinase
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
AKT
cervical cancer
human papillomavirus
tumor virus
Journal
mBio
ISSN: 2150-7511
Titre abrégé: mBio
Pays: United States
ID NLM: 101519231
Informations de publication
Date de publication:
12 02 2019
12 02 2019
Historique:
entrez:
14
2
2019
pubmed:
14
2
2019
medline:
29
3
2019
Statut:
epublish
Résumé
Hypoxia is linked to therapeutic resistance and poor clinical prognosis for many tumor entities, including human papillomavirus (HPV)-positive cancers. Notably, HPV-positive cancer cells can induce a dormant state under hypoxia, characterized by a reversible growth arrest and strong repression of viral E6/E7 oncogene expression, which could contribute to therapy resistance, immune evasion and tumor recurrence. The present work aimed to gain mechanistic insights into the pathway(s) underlying HPV oncogene repression under hypoxia. We show that E6/E7 downregulation is mediated by hypoxia-induced stimulation of AKT signaling. Ablating AKT function in hypoxic HPV-positive cancer cells by using chemical inhibitors efficiently counteracts E6/E7 repression. Isoform-specific activation or downregulation of AKT1 and AKT2 reveals that both AKT isoforms contribute to hypoxic E6/E7 repression and act in a functionally redundant manner. Hypoxic AKT activation and consecutive E6/E7 repression is dependent on the activities of the canonical upstream AKT regulators phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) complex 2 (mTORC2). Hypoxic downregulation of E6/E7 occurs, at least in part, at the transcriptional level. Modulation of E6/E7 expression by the PI3K/mTORC2/AKT cascade is hypoxia specific and not observed in normoxic HPV-positive cancer cells. Quantitative proteome analyses identify additional factors as candidates to be involved in hypoxia-induced activation of the PI3K/mTORC2/AKT signaling cascade and in the AKT-dependent repression of the E6/E7 oncogenes under hypoxia. Collectively, these data uncover a functional key role of the PI3K/mTORC2/AKT signaling cascade for viral oncogene repression in hypoxic HPV-positive cancer cells and provide new insights into the poorly understood cross talk between oncogenic HPVs and their host cells under hypoxia.
Identifiants
pubmed: 30755508
pii: mBio.02323-18
doi: 10.1128/mBio.02323-18
pmc: PMC6372795
pii:
doi:
Substances chimiques
Oncogene Proteins, Viral
0
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
AKT1 protein, human
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2019 Bossler et al.
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