Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies

Abstract

Background: Hypoxia is a negative prognostic factor and this study investigated the relationship between hypoxia, hypoxia inducible factor 1 (HIF-1) and AKT signaling in head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC). Results/methodology: pAKT was induced by hypoxia (0.5% O₂) in a part of HNSCC (3/4) and squamous (2/3) and adenocarcinoma (1/3) NSCLS lines. AKT-inhibitor MK-2206 reduced hypoxic HIF-1 signaling in most HNSCC cell lines. This reduction did not correlate with hypoxic induction of pAKT or with sensitivity to MK-2206 under hypoxia. Patient biopsies revealed a hypoxia-induced expression pattern of pAKT in HNSCC (n = 16), which was not observed in squamous cell (n = 34) or adenocarcinoma (n = 41) NSCLC. Conclusion: The interaction between hypoxia, HIF-1 and AKT signaling varies between tumor types and histologies, which could significantly affect response to targeted therapies.

Lay abstract: Hypoxia is the result of an imbalance between oxygen delivery and oxygen consumption, and hypoxic areas are a common feature in solid tumors, including head and neck and lung cancer. Hypoxia activates various signaling pathways that enhance the survival of tumor cells (e.g., HIF-1 and AKT) and is, therefore, an inherent negative factor for outcome. In this study, we show that the interaction between hypoxia and these pathways varies widely between tumor types and histologies. This variation could significantly affect response to treatments targeting hypoxia or these signaling pathways.

Keywords::

• adenocarcinoma
• AKT
• HIF-1
• HNSCC
• hypoxia
• NSCLC
• squamous cell carcinoma

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.4155/fso.15.84

Acknowledgements

The authors would like to acknowledge the excellent technical assistance of J Lok and H Peters of the department of Radiation Oncology in Nijmegen.

Author contributions

H Stegeman, PN Span, JHAM Kaanders and J Bussink were involved in the design of the experiments, interpretation of the data and writing the article. H Stegeman, Wenny JM Peeters, MMG Verheijen and TWH Meijer were involved in the acquisition and analysis of the data. R Grénman made important resources (cell lines) available. All authors were involved in revising the draft and approved the final version of the draft.

Financial & competing interests disclosure

The authors have received funding from the Dutch Cancer Society, grant number 2008-4000. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Open access

This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/