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  • Original Paper
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Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics

Oncogene volume 21, pages 1882–1889 (2002)Cite this article

Abstract

We recently identified inositol hexakisphosphate kinase 2 (IP6K2) as a positive regulator of apoptosis. Overexpression of IP6K2 enhances apoptosis induced by interferon-β (IFN-β) and cytotoxic agents in NIH-OVCAR-3 ovarian carcinoma cells. In this study, we contrast and compare IFN-β and radiation-induced death, and show that IP6K2 expression sensitizes tumor cells. Unirradiated NIH-OVCAR-3 cells transfected with IP6K2 formed fewer colonies compared to unirradiated vector-expressing cells. IP6K2 overexpression caused increased radiosensitivity, evidenced by decreased colony forming units (CFU). Both IFN-β and radiation induced caspase 8. IFN-β, but not γ-irradiation, induced TRAIL in NIH-OVCAR-3 cells. Gamma irradiation, but not IFN-β, induced DR4 mRNA. Apoptotic effects of IFN-β or γ-irradiation were blocked by expression of a dominant negative mutant death receptor 5 (DR5Δ) or by Bcl-2. Caspase-8 mRNA induction was more pronounced in IP6K2-expressing cells compared to vector-expressing cells. These data suggest that overexpression of IP6K2 enhances sensitivity of some ovarian carcinomas to radiation and IFN-β. IP6K2 may function to enhance the expression and/or function of caspase 8 and DR4 following cell injury. Both IFN-β and γ-irradiation induce apoptosis through the extrinsic, receptor-mediated pathway, IFN-β through TRAIL, radiation through DR4, and both through caspase 8. The function of both death inducers is positively regulated by IP6K2.

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Abbreviations

AFC:

7-amino-4-trifluoromethyl coumarin

CFU:

colony forming unit

DISC:

death-inducing signaling complex

DR:

death receptor

DMF:

dose modification factor

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase; Gy, gray

IETD:

Ile-Glu-Thr-Asp

IFN:

interferon

IP6K2:

inositol hexakisphosphate kinase 2

RPA:

ribonuclease protection assay

SRB:

sulforhodamine B

TRAIL:

TNF-related apoptosis-inducing ligand

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Acknowledgements

These studies were supported by a grant from the Taussig Cancer Center Bridge Grant Program to D Lindner. A Almasan was supported by grants from National Institutes of Health (CA81504 and CA82858). D Kalvakolanu was supported by grants from NCI and NIH (CA71401 and CA78282). We thank Drs ES Alnemri and SM Srinivasula (T Jefferson) for the DR5Δ construct.

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Authors and Affiliations

  1. Center for Cancer Drug Discovery and Development, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Bei H Morrison, Joseph A Bauer, Ronald W Grane, Aylin M Ozdemir, Mamta Chawla-Sarkar & Daniel J Lindner

  2. Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Bendi Gong, Alex Almasan & Daniel J Lindner

  3. Department of Radiation Oncology, The Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

    Alex Almasan

  4. Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, 21201, Maryland, MD, USA

    Jiadi Hu & Dhananjaya V Kalvakolanu

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  1. Bei H Morrison
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  2. Joseph A Bauer
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Correspondence to Daniel J Lindner.

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Morrison, B., Bauer, J., Hu, J. et al. Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics. Oncogene 21, 1882–1889 (2002). https://doi.org/10.1038/sj.onc.1205265

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