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  • Original Article
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Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma

Oncogene volume 28, pages 2383–2392 (2009)Cite this article

Abstract

Inositol hexakisphosphate kinase 2 (IP6K2), a member of the inositol hexakisphosphate kinase family, functions as a growth suppressive and apoptosis-enhancing kinase during cell stress. We created mice with a targeted deletion of IP6K2; these mice display normal embryogenesis, development, growth and fertility. Chronic exposure to the carcinogen 4-nitroquinoline 1-oxide (4-NQO, a UV-mimetic compound) in drinking water resulted in fourfold increased incidence of invasive squamous cell carcinoma (SCC) formation in the oral cavity and esophagus of the knockout (KO) mice compared to the wild-type (WT) littermates. Paradoxically, KO mice displayed relative resistance to ionizing radiation and exhibit enhanced survival following 8–10 Gy total body irradiation. Primary KO fibroblasts displayed resistance to antiproliferative effects of interferon-β and increased colony forming units following ionizing radiation. Radioresistance of KO fibroblasts was associated with accelerated DNA repair measured by comet assay. Direct microinjection of 5-PP-Ins(1,2,3,4,6)P5 (the enzymatic product of IP6K2), but not InsP6 (the substrate of IP6K2) induced cell death in SCC22A squamous carcinoma cells.

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Abbreviations

IP6K2:

inositol hexakisphosphate kinase 2

4-NQO:

4-nitroquinoline 1-oxide

IFN:

interferon

HNSCC:

head and neck squamous cell carcinoma

NHEJ:

nonhomologous end joining

PBS:

phosphate-buffered saline

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Acknowledgements

We thank Philip Sanford, University of Cincinnati, for design of targeting vector and creation of IHPK2 knockout mice. Donna Kusewitt, Ohio State University, Director, Mouse Phenotyping Shared Resource, kusewitt.1@osu.edu, conducted the phenotyping studies. Judy Drazba, Cleveland Clinic Imaging Core, performed the time-lapse photography of microinjected cells. Dr Yong Xu, Dr Honglu Zhang and Dr Jianxing Zhang performed the synthesis of 5-PP-Ins(1,2,3,4,6)P5. These studies were supported by grants from NIH/NCI (CA095020) to DJL and from NIH (NS29632) to GDP.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    B H Morrison, R Haney, E Lamarre & D J Lindner

  2. Head and Neck Institute, Cleveland Clinic, Cleveland, OH, USA

    E Lamarre

  3. Research Core Administration, Cleveland Clinic, Cleveland, OH, USA

    J Drazba

  4. University of Utah Health Sciences Center, Salt Lake City, UT, USA

    G D Prestwich

  5. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    D J Lindner

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  1. B H Morrison
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  2. R Haney
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  6. D J Lindner
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Correspondence to D J Lindner.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Morrison, B., Haney, R., Lamarre, E. et al. Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma. Oncogene 28, 2383–2392 (2009). https://doi.org/10.1038/onc.2009.113

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