P1 Downregulation of hypoxia-inducible factor 1 α expression inhibits growth and enhances IGF1R inhibitor OSI906 sensitivity in head and neck squamous cell carcinoma cells
Ashraf Khalil1,2, Mark Jameson1
1Department of Clinical Biochemistry and Molecular Diagnostics, National Liver Institute, Menoufia University, Shebin ELkom, Egypt; 2Department of Otolaryngology – Head and Neck Surgery. University of Virginia, Charlottesville, Virginia, USA
Correspondence: Ashraf Khalil (email@example.com)
Hypoxia-inducible factor 1 α (HIF‑1α) is a central regulator for cells to adapt to low cellular oxygen levels, is also often overexpressed and activated in many human cancers. HIF‑1α mediates the primary transcriptional response of a wide range of genes in response to hypoxia. Insulin‑like growth factor‑1 receptor (IGF‑1R) is a cell membrane receptor involved in cell proliferation is expressed in the head and squamous cell carcinoma.
To detect the effect of HIF‑1α downregulation on the sensitivity of squamous cell carcinoma (SCC) to small molecule IGF1R inhibitor OSI-906.
A lentivirus-mediated doxycycline-inducible pTRIPZ short hairpin RNA micro (shRNAmir) plasmid targeting HIF‑1α was transfected into two head and neck squamous cell carcinoma (HNSCC) cell lines to silence HIF‑1α expression and to assess the effect of its downregulation on cell proliferation and sensitivity to IGF1R inhibitor. A nude mice animal model was developed by the transfection of a luciferase gene into the inducible shRNA HIF‑1α cells and growing tumors by direct inoculation of the cells in the tongue. Tumor growth was determined by detecting the bioluminescence signal by the advanced IVIS 200 technology (Figure 2d).
Downregulation of the expression of HIF‑1α (Figure1 a-b) led to an increase in the sensitivity of head and neck squamous cell carcinoma to the OSI-906 IGF1R small molecule inhibitor (Figure 2a-b) by a mechanism involving the increase in apoptosis (Figure 2c).
The preliminary findings suggest that co-targeting of IGF‑1R and HIF‑1α may represent a novel approach for resistant head and neck tumors.
This study received supported from the National Institutes of Health (NIH) (K08 grant DE019477) (M.J.J.) and the University of Virginia (UVA) Cancer Center/UVA Department of Otolaryngology–Head and Neck Surgery Pilot Project Grant (M.J.J./D.G.G.). The authors have no other funding, financial relationships, or conflicts of interest to disclose.