Synergistic effect of 15-lipoxygenase 2 and radiation in killing head-and-neck cancer.
We previously demonstrated that 15-LOX-2 is significantly reduced in head and neck carcinoma and restoration of 15-LOX-2 expression results in tumor inhibition in HNC. The aim of this study is to evaluate 15-LOX-2 as a candidate for targeted radiotherapy. Molecular subcloning was performed to create a radiation-inducible 15-LOX-2 expression vector in which the full-length 15-LOX-2 cDNA was inserted downstream the recombinant Egr-1 promoter. The radiation-induced downregulations of 15-LOX-2 protein (twofold up) and its main metabolite 15S-HETE (threefold up) were observed in HNC cells transfected with the 15-LOX-2 expression vector after 4 Gy of radiation. Radiation-induced upregulation of 15-LOX-2 resulted in significant induction of apoptosis in HNC cells. Furthermore, survival colony formation was significantly reduced by 4 Gy in the HNC cells containing the 15-LOX-2 expression vector compared with the controls. Radiation-induced upregulation of 15-LOX-2 results in significant induction of apoptosis and enhances killing effect of radiotherapy in HNC. In addition, exogenous addition of 15S-HETE at high concentrations (>/=10 muM) but not at low concentrations induced upregulation of its endogenous ligand PPARgamma. In conclusion, synergistic effect between radiation and 15-LOX-2 was observed in killing HNC. 15-LOX-2 may be a potential target in radiation-targeted therapy of HNC. The 15-LOX-2 inhibition may not be PPARgamma dependent.
Yang
Q
Q
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Feng
Y
Y
Schultz
C J
CJ
Li
X A
XA
Wu
H
H
Wang
D
D
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000235:genetics; D017930:Genes, Reporter; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008084:Lipoxygenase / Q000235:genetics / Q000627:therapeutic use*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic
D008084:Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D008156:Luciferases; C512478:EGFR protein, human; D066246:ErbB Receptors