Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics.
We recently identified inositol hexakisphosphate kinase 2 (IP6K2) as a positive regulator of apoptosis. Overexpression of IP6K2 enhances apoptosis induced by interferon-beta (IFN-beta) and cytotoxic agents in NIH-OVCAR-3 ovarian carcinoma cells. In this study, we contrast and compare IFN-beta 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-beta and radiation induced caspase 8. IFN-beta, but not gamma-irradiation, induced TRAIL in NIH-OVCAR-3 cells. Gamma irradiation, but not IFN-beta, induced DR4 mRNA. Apoptotic effects of IFN-beta or gamma-irradiation were blocked by expression of a dominant negative mutant death receptor 5 (DR5Delta) 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-beta. IP6K2 may function to enhance the expression and/or function of caspase 8 and DR4 following cell injury. Both IFN-beta and gamma-irradiation induce apoptosis through the extrinsic, receptor-mediated pathway, IFN-beta through TRAIL, radiation through DR4, and both through caspase 8. The function of both death inducers is positively regulated by IP6K2.
Morrison
Bei H
BH
Center for Cancer Drug Discovery and Development, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, Ohio, OH 44195, USA.
Bauer
Joseph A
JA
Hu
Jiadi
J
Grane
Ronald W
RW
Ozdemir
Aylin M
AM
Chawla-Sarkar
Mamta
M
Gong
Bendi
B
Almasan
Alex
A
Kalvakolanu
Dhananjaya V
DV
Lindner
Daniel J
DJ
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D016899:Interferon-beta; D017856:Phosphotransferases (Phosphate Group Acceptor); C115134:IP6K1 protein, human; D012260:Ribonucleases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases