Abstract
Human papillomavirus (HPV)-induced cancers will remain a significant clinical challenge for decades. Thus, the development of novel treatment strategies is urgently required, which should benefit from improving our understanding of the mechanisms of HPV-induced cell transformation. This should also include analyses of hypoxic tumor cells, which represent a major problem for cancer therapy. Recent evidence indicates that the PI3K/AKT/mTOR network plays a key role for the virus/host cell crosstalk in both normoxic and hypoxic HPV-positive cancer cells. In normoxic cells, the efficacy of the senescence induction upon experimental E6/E7 repression depends on active mTORC1 signaling. Under hypoxia, however, HPV-positive cancer cells can evade senescence due to hypoxic impairment of mTORC1 signaling, albeit the cells strongly downregulate E6/E7. Hypoxic repression of E6/E7 is mediated by the AKT kinase, which is activated under hypoxia by its canonical upstream regulators mTORC2 and PI3K. This review highlights our current knowledge about the oxygen-dependent crosstalk of the PI3K/AKT/mTOR signaling circuit with the HPV oncogenes and the phenotypic state of the host cell. Moreover, since the PI3K/AKT/mTOR pathway is considered to be a promising target for anticancer therapy, we discuss clinical implications for the treatment of HPV-positive cervical and head and neck squamous cell carcinomas.
Highlights
Human papillomaviruses (HPVs) are major risk factors for the development of oropharyngeal and anogenital cancers
Recent findings reveal that there is a complex interplay between the phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) signaling cascade, the regulation of HPV oncogene expression and the phenotypic response of HPV-positive cancer cells to E6/E7 repression, which all are dependent on the cellular metabolic and oxygenation status [4,18,19,25]
The PI3K/AKT/mTOR signaling cascade plays a key role in the virus/host cell crosstalk of HPV-positive cancer cells
Summary
Human papillomaviruses (HPVs) are major risk factors for the development of oropharyngeal and anogenital cancers. Since -upon reoxygenation- dormant HPV-positive cancer cells can reactivate E6/E7 expression and resume proliferation, this cell population may serve as a reservoir for tumor recurrence after treatment [19] These findings show that, in order to improve the treatment outcome, it is of great importance to develop therapeutic strategies that are effective against hypoxic cancer cells. Recent findings reveal that there is a complex interplay between the PI3K/AKT/mTOR signaling cascade, the regulation of HPV oncogene expression and the phenotypic response of HPV-positive cancer cells to E6/E7 repression, which all are dependent on the cellular metabolic and oxygenation status [4,18,19,25]. The PI3K/AKT/mTOR signaling cascade influences many fundamental aspects of cellular biology by promoting cell survival, growth, proliferation, migration and energy metabolism Aberrant activation of this pathway can contribute to the malignant phenotype of tumor cells and to therapy resistance.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
