Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma.
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-beta 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)P(5) (the enzymatic product of IP6K2), but not InsP(6) (the substrate of IP6K2) induced cell death in SCC22A squamous carcinoma cells.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
B H
BH
Morrison
R
R
Haney
E
E
Lamarre
J
J
Drazba
G D
GD
Prestwich
D J
DJ
Lindner
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000532:radiotherapy; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005720:Gamma Rays; D017353:Gene Deletion; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009062:Mouth Neoplasms / Q000235:genetics*; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D015112:4-Nitroquinoline-1-oxide; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase